WO2024118936A1 - Composés de 2-arylbenzimidazole pour le traitement d'hémoglobinopathies - Google Patents
Composés de 2-arylbenzimidazole pour le traitement d'hémoglobinopathies Download PDFInfo
- Publication number
- WO2024118936A1 WO2024118936A1 PCT/US2023/081849 US2023081849W WO2024118936A1 WO 2024118936 A1 WO2024118936 A1 WO 2024118936A1 US 2023081849 W US2023081849 W US 2023081849W WO 2024118936 A1 WO2024118936 A1 WO 2024118936A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- benzo
- alkoxy
- imidazole
- tert
- Prior art date
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- 208000034737 hemoglobinopathy Diseases 0.000 title claims abstract description 52
- 208000018337 inherited hemoglobinopathy Diseases 0.000 title abstract description 15
- UXGJAOIJSROTTN-UHFFFAOYSA-N 2-[4-(4-chlorophenoxy)phenyl]-3h-benzimidazole-5-carboxamide Chemical class N1C2=CC(C(=O)N)=CC=C2N=C1C(C=C1)=CC=C1OC1=CC=C(Cl)C=C1 UXGJAOIJSROTTN-UHFFFAOYSA-N 0.000 title abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 96
- 208000007056 sickle cell anemia Diseases 0.000 claims abstract description 53
- 238000004519 manufacturing process Methods 0.000 claims abstract description 40
- 230000001965 increasing effect Effects 0.000 claims abstract description 32
- 108010044495 Fetal Hemoglobin Proteins 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims description 183
- -1 hydroxy, carboxy Chemical group 0.000 claims description 180
- LQUNNCQSFFKSSK-UHFFFAOYSA-N 2-(4-tert-butylphenyl)-1h-benzimidazole Chemical compound C1=CC(C(C)(C)C)=CC=C1C1=NC2=CC=CC=C2N1 LQUNNCQSFFKSSK-UHFFFAOYSA-N 0.000 claims description 175
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 162
- 150000001875 compounds Chemical class 0.000 claims description 156
- 239000000203 mixture Substances 0.000 claims description 149
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 145
- 229910052739 hydrogen Inorganic materials 0.000 claims description 120
- 239000001257 hydrogen Substances 0.000 claims description 117
- 239000002552 dosage form Substances 0.000 claims description 103
- 239000007962 solid dispersion Substances 0.000 claims description 97
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 80
- 229910052757 nitrogen Inorganic materials 0.000 claims description 67
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 58
- 229910052805 deuterium Inorganic materials 0.000 claims description 58
- 239000011159 matrix material Substances 0.000 claims description 56
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 54
- 229910052736 halogen Inorganic materials 0.000 claims description 45
- 150000002367 halogens Chemical class 0.000 claims description 45
- 239000003937 drug carrier Substances 0.000 claims description 44
- 229920000642 polymer Polymers 0.000 claims description 43
- 239000003085 diluting agent Substances 0.000 claims description 41
- 125000003282 alkyl amino group Chemical group 0.000 claims description 40
- 150000003839 salts Chemical class 0.000 claims description 40
- 229920001223 polyethylene glycol Polymers 0.000 claims description 39
- 239000002202 Polyethylene glycol Substances 0.000 claims description 38
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 38
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 38
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 37
- 229920002554 vinyl polymer Polymers 0.000 claims description 37
- 125000006657 (C1-C10) hydrocarbyl group Chemical group 0.000 claims description 36
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 35
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 32
- 238000009474 hot melt extrusion Methods 0.000 claims description 32
- 239000007884 disintegrant Substances 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 30
- 239000000314 lubricant Substances 0.000 claims description 28
- 235000003599 food sweetener Nutrition 0.000 claims description 27
- 239000003765 sweetening agent Substances 0.000 claims description 27
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 26
- 239000008187 granular material Substances 0.000 claims description 25
- 239000000843 powder Substances 0.000 claims description 25
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 23
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 23
- 150000002825 nitriles Chemical class 0.000 claims description 22
- 239000013543 active substance Substances 0.000 claims description 21
- 125000002252 acyl group Chemical group 0.000 claims description 21
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 21
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 21
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 21
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 21
- 239000000651 prodrug Substances 0.000 claims description 21
- 229940002612 prodrug Drugs 0.000 claims description 21
- 239000012453 solvate Substances 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 125000004442 acylamino group Chemical group 0.000 claims description 20
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 20
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 20
- 125000004414 alkyl thio group Chemical group 0.000 claims description 20
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 20
- 150000003857 carboxamides Chemical class 0.000 claims description 20
- 125000005518 carboxamido group Chemical group 0.000 claims description 20
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 20
- 229920000578 graft copolymer Polymers 0.000 claims description 20
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 19
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 19
- 229910014033 C-OH Inorganic materials 0.000 claims description 18
- 125000006416 CBr Chemical group BrC* 0.000 claims description 18
- 229910014570 C—OH Inorganic materials 0.000 claims description 18
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 18
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 18
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- 239000004094 surface-active agent Substances 0.000 claims description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 16
- 125000000623 heterocyclic group Chemical group 0.000 claims description 16
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 16
- 125000006519 CCH3 Chemical group 0.000 claims description 14
- 125000006414 CCl Chemical group ClC* 0.000 claims description 14
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 14
- 229920001531 copovidone Polymers 0.000 claims description 14
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 13
- 229910021486 amorphous silicon dioxide Inorganic materials 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 13
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 13
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 13
- 229940069328 povidone Drugs 0.000 claims description 13
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 12
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 11
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 11
- 229920001577 copolymer Polymers 0.000 claims description 11
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 11
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 11
- 238000001694 spray drying Methods 0.000 claims description 11
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 claims description 10
- 239000011230 binding agent Substances 0.000 claims description 10
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 10
- 229960001330 hydroxycarbamide Drugs 0.000 claims description 10
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 9
- 125000006624 (C1-C6) alkoxycarbonylamino group Chemical group 0.000 claims description 9
- 229920000881 Modified starch Polymers 0.000 claims description 9
- 208000000859 Sickle cell trait Diseases 0.000 claims description 9
- 150000001413 amino acids Chemical class 0.000 claims description 9
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 9
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 9
- FWCVZAQENIZVMY-UHFFFAOYSA-N 2-hydroxy-6-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]benzaldehyde Chemical compound CC(C)N1N=CC=C1C1=NC=CC=C1COC1=CC=CC(O)=C1C=O FWCVZAQENIZVMY-UHFFFAOYSA-N 0.000 claims description 8
- 208000002903 Thalassemia Diseases 0.000 claims description 8
- 229950004730 crizanlizumab Drugs 0.000 claims description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- 229940100692 oral suspension Drugs 0.000 claims description 8
- 239000004014 plasticizer Substances 0.000 claims description 8
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 8
- 239000000454 talc Substances 0.000 claims description 8
- 229910052623 talc Inorganic materials 0.000 claims description 8
- 235000012222 talc Nutrition 0.000 claims description 8
- 229940070141 voxelotor Drugs 0.000 claims description 8
- HWDUHGRTMKGOFF-UHFFFAOYSA-N 2-(4-tert-butylphenyl)-3H-benzimidazol-5-ol Chemical compound C1=CC(C(C)(C)C)=CC=C1C1=NC2=CC=C(O)C=C2N1 HWDUHGRTMKGOFF-UHFFFAOYSA-N 0.000 claims description 7
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 6
- 229930195725 Mannitol Natural products 0.000 claims description 6
- 206010040642 Sickle cell anaemia with crisis Diseases 0.000 claims description 6
- 229960002743 glutamine Drugs 0.000 claims description 6
- 239000000594 mannitol Substances 0.000 claims description 6
- 235000010355 mannitol Nutrition 0.000 claims description 6
- 235000000346 sugar Nutrition 0.000 claims description 6
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 claims description 5
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 5
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 5
- 229930182816 L-glutamine Natural products 0.000 claims description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 5
- 208000005980 beta thalassemia Diseases 0.000 claims description 5
- 235000010980 cellulose Nutrition 0.000 claims description 5
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- 229960001375 lactose Drugs 0.000 claims description 5
- 239000008101 lactose Substances 0.000 claims description 5
- 229960001021 lactose monohydrate Drugs 0.000 claims description 5
- 235000019739 Dicalciumphosphate Nutrition 0.000 claims description 4
- 208000034502 Haemoglobin C disease Diseases 0.000 claims description 4
- 108010016797 Sickle Hemoglobin Proteins 0.000 claims description 4
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 4
- 239000001506 calcium phosphate Substances 0.000 claims description 4
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 claims description 4
- 229940038472 dicalcium phosphate Drugs 0.000 claims description 4
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 4
- 229910000390 dicalcium phosphate Inorganic materials 0.000 claims description 4
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- 239000003381 stabilizer Substances 0.000 claims description 4
- 150000008163 sugars Chemical class 0.000 claims description 4
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 4
- 235000019731 tricalcium phosphate Nutrition 0.000 claims description 4
- 235000021355 Stearic acid Nutrition 0.000 claims description 3
- 239000003963 antioxidant agent Substances 0.000 claims description 3
- 239000008122 artificial sweetener Substances 0.000 claims description 3
- 235000021311 artificial sweeteners Nutrition 0.000 claims description 3
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 3
- 239000008116 calcium stearate Substances 0.000 claims description 3
- 235000013539 calcium stearate Nutrition 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 229960000913 crospovidone Drugs 0.000 claims description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 3
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 3
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- 229940079832 sodium starch glycolate Drugs 0.000 claims description 3
- 239000008117 stearic acid Substances 0.000 claims description 3
- YWNXHTNWOQHFRL-UHFFFAOYSA-N 2-(1H-benzimidazol-2-yl)aniline Chemical compound NC1=CC=CC=C1C1=NC2=CC=CC=C2N1 YWNXHTNWOQHFRL-UHFFFAOYSA-N 0.000 claims description 2
- KOXRUUGKLDCECO-UHFFFAOYSA-N 2-(2-bromophenyl)-1h-benzimidazole Chemical compound BrC1=CC=CC=C1C1=NC2=CC=CC=C2N1 KOXRUUGKLDCECO-UHFFFAOYSA-N 0.000 claims description 2
- OILIYWFQRJOPAI-UHFFFAOYSA-N 2-(2-chlorophenyl)-1h-benzimidazole Chemical compound ClC1=CC=CC=C1C1=NC2=CC=CC=C2N1 OILIYWFQRJOPAI-UHFFFAOYSA-N 0.000 claims description 2
- ASFACGIBGAEFHS-UHFFFAOYSA-N 2-(2-fluorophenyl)-1h-benzimidazole Chemical compound FC1=CC=CC=C1C1=NC2=CC=CC=C2N1 ASFACGIBGAEFHS-UHFFFAOYSA-N 0.000 claims description 2
- JNFBDHNAZPBWTF-UHFFFAOYSA-N 2-(2-methoxyphenyl)-1h-benzimidazole Chemical compound COC1=CC=CC=C1C1=NC2=CC=CC=C2N1 JNFBDHNAZPBWTF-UHFFFAOYSA-N 0.000 claims description 2
- XBXVUKKKEYEPTR-UHFFFAOYSA-N 2-(2-methylphenyl)-1h-benzimidazole Chemical compound CC1=CC=CC=C1C1=NC2=CC=CC=C2N1 XBXVUKKKEYEPTR-UHFFFAOYSA-N 0.000 claims description 2
- GUOMCHPWZHFOQZ-UHFFFAOYSA-N 2-(3,5-ditert-butylphenyl)-1h-benzimidazole Chemical compound CC(C)(C)C1=CC(C(C)(C)C)=CC(C=2NC3=CC=CC=C3N=2)=C1 GUOMCHPWZHFOQZ-UHFFFAOYSA-N 0.000 claims description 2
- KLPQPEGYDCWTKZ-UHFFFAOYSA-N 2-(3-bromophenyl)-1h-benzimidazole Chemical compound BrC1=CC=CC(C=2NC3=CC=CC=C3N=2)=C1 KLPQPEGYDCWTKZ-UHFFFAOYSA-N 0.000 claims description 2
- BGYHTIIVIGGCIF-UHFFFAOYSA-N 2-(3-chlorophenyl)-1h-benzimidazole Chemical compound ClC1=CC=CC(C=2NC3=CC=CC=C3N=2)=C1 BGYHTIIVIGGCIF-UHFFFAOYSA-N 0.000 claims description 2
- WNDVNZISLWPOLI-UHFFFAOYSA-N 2-(3-fluorophenyl)-1h-benzimidazole Chemical compound FC1=CC=CC(C=2NC3=CC=CC=C3N=2)=C1 WNDVNZISLWPOLI-UHFFFAOYSA-N 0.000 claims description 2
- XAMZPXRUPPCGFJ-UHFFFAOYSA-N 2-(3-methoxyphenyl)-1h-benzimidazole Chemical compound COC1=CC=CC(C=2NC3=CC=CC=C3N=2)=C1 XAMZPXRUPPCGFJ-UHFFFAOYSA-N 0.000 claims description 2
- USLJYASOSQJYGN-UHFFFAOYSA-N 2-(3-methylphenyl)-1h-benzimidazole Chemical compound CC1=CC=CC(C=2NC3=CC=CC=C3N=2)=C1 USLJYASOSQJYGN-UHFFFAOYSA-N 0.000 claims description 2
- HARDIOAREZHDBF-UHFFFAOYSA-N 2-(3-tert-butylphenyl)-1h-benzimidazole Chemical compound CC(C)(C)C1=CC=CC(C=2NC3=CC=CC=C3N=2)=C1 HARDIOAREZHDBF-UHFFFAOYSA-N 0.000 claims description 2
- MPSHIXMEXRCCCA-UHFFFAOYSA-N 2-(3-tert-butylphenyl)-4,6-difluoro-1H-benzimidazole Chemical compound C(C)(C)(C)C=1C=C(C=CC=1)C1=NC2=C(N1)C=C(C=C2F)F MPSHIXMEXRCCCA-UHFFFAOYSA-N 0.000 claims description 2
- YRWMGOSKROWAIT-UHFFFAOYSA-N 2-(4-bromophenyl)-1h-benzimidazole Chemical compound C1=CC(Br)=CC=C1C1=NC2=CC=CC=C2N1 YRWMGOSKROWAIT-UHFFFAOYSA-N 0.000 claims description 2
- PTXUJRTVWRYYTE-UHFFFAOYSA-N 2-(4-chlorophenyl)-1h-benzimidazole Chemical compound C1=CC(Cl)=CC=C1C1=NC2=CC=CC=C2N1 PTXUJRTVWRYYTE-UHFFFAOYSA-N 0.000 claims description 2
- SQFPPQMOGHWXLU-UHFFFAOYSA-N 2-(4-ethoxyphenyl)-1h-benzimidazole Chemical compound C1=CC(OCC)=CC=C1C1=NC2=CC=CC=C2N1 SQFPPQMOGHWXLU-UHFFFAOYSA-N 0.000 claims description 2
- SGMVEXZRDKPEJI-UHFFFAOYSA-N 2-(4-ethylphenyl)-1h-benzimidazole Chemical compound C1=CC(CC)=CC=C1C1=NC2=CC=CC=C2N1 SGMVEXZRDKPEJI-UHFFFAOYSA-N 0.000 claims description 2
- FPWUSPPQEHBWHC-UHFFFAOYSA-N 2-(4-fluorophenyl)-1h-benzimidazole Chemical compound C1=CC(F)=CC=C1C1=NC2=CC=CC=C2N1 FPWUSPPQEHBWHC-UHFFFAOYSA-N 0.000 claims description 2
- PYRWEZBEXFMUHH-UHFFFAOYSA-N 2-(4-methoxyphenyl)-1h-benzimidazole Chemical compound C1=CC(OC)=CC=C1C1=NC2=CC=CC=C2N1 PYRWEZBEXFMUHH-UHFFFAOYSA-N 0.000 claims description 2
- YJSWQFYMPODDTQ-UHFFFAOYSA-N 2-(4-methylphenyl)-1h-benzimidazole Chemical compound C1=CC(C)=CC=C1C1=NC2=CC=CC=C2N1 YJSWQFYMPODDTQ-UHFFFAOYSA-N 0.000 claims description 2
- SJQYEMCIARWWGD-UHFFFAOYSA-N 2-(4-phenylmethoxyphenyl)-1h-benzimidazole Chemical compound C=1C=C(C=2NC3=CC=CC=C3N=2)C=CC=1OCC1=CC=CC=C1 SJQYEMCIARWWGD-UHFFFAOYSA-N 0.000 claims description 2
- MTLATYGCQJNGKY-UHFFFAOYSA-N 2-(4-propan-2-yloxyphenyl)-1h-benzimidazole Chemical compound C1=CC(OC(C)C)=CC=C1C1=NC2=CC=CC=C2N1 MTLATYGCQJNGKY-UHFFFAOYSA-N 0.000 claims description 2
- KZLWMCPIYIDTTK-UHFFFAOYSA-N 2-(4-propan-2-ylphenyl)-1h-benzimidazole Chemical compound C1=CC(C(C)C)=CC=C1C1=NC2=CC=CC=C2N1 KZLWMCPIYIDTTK-UHFFFAOYSA-N 0.000 claims description 2
- AGSYKXRBABATDL-UHFFFAOYSA-N 2-(4-propoxyphenyl)-1h-benzimidazole Chemical compound C1=CC(OCCC)=CC=C1C1=NC2=CC=CC=C2N1 AGSYKXRBABATDL-UHFFFAOYSA-N 0.000 claims description 2
- RBKGJKUWWDNBNT-UHFFFAOYSA-N 2-(4-tert-butylphenyl)-1,3-benzothiazole Chemical compound C1=CC(C(C)(C)C)=CC=C1C1=NC2=CC=CC=C2S1 RBKGJKUWWDNBNT-UHFFFAOYSA-N 0.000 claims description 2
- ZNBHIZVPIRZVLA-UHFFFAOYSA-N 2-(4-tert-butylphenyl)-1,3-benzoxazole Chemical compound C1=CC(C(C)(C)C)=CC=C1C1=NC2=CC=CC=C2O1 ZNBHIZVPIRZVLA-UHFFFAOYSA-N 0.000 claims description 2
- RLPWKCKVOHRQCR-UHFFFAOYSA-N 2-(4-tert-butylphenyl)-1H-benzimidazol-4-amine Chemical compound C1=CC(C(C)(C)C)=CC=C1C1=NC2=C(N)C=CC=C2N1 RLPWKCKVOHRQCR-UHFFFAOYSA-N 0.000 claims description 2
- HMRLUZXGRXGFCQ-UHFFFAOYSA-N 2-(4-tert-butylphenyl)-1H-benzimidazol-4-ol Chemical compound CC(C)(C)C1=CC=C(C=C1)C1=NC2=C(O)C=CC=C2N1 HMRLUZXGRXGFCQ-UHFFFAOYSA-N 0.000 claims description 2
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- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
Definitions
- Hemoglobinopathies encompass a number of anemias of genetic origin in which there is a decreased production of red blood cells (RBCs) and/or increased destruction (hemolysis) of RBCs. Hemoglobinopathies also include genetic defects that result in the production of abnormal hemoglobins with a concomitant impaired ability to maintain oxygen concentration. Some such disorders involve the failure to produce normal ⁇ -globin in sufficient amounts, while others involve the failure to produce normal ⁇ -globin entirely. These disorders associated with the ⁇ -globin protein are referred to generally as ⁇ -hemoglobinopathies.
- HbA hemoglobin A
- HbS herniated hemoglobin
- HbS RBCs are more fragile than normal RBCs and undergo hemolysis more readily, leading eventually to anemia. Sickling of RBCs in blood vessels also leads to impairment in blood flow (vaso-occlusion), with resulting ischemia, endothelial injury, and sterile inflammation in multiple organs.
- sickle cell disease SCD
- SCA sickle-cell anemia
- SRBC sickle red blood cells
- Oral administration is preferred to parenteral administration for chronic life-long treatment, as is required for treating hemoglobinopathies such as sickle cell disease.
- ZLN-005/TQS-168 is poorly soluble, making formulation for oral administration difficult. There is a need, therefore, for agents that increase PGC-1 ⁇ expression that can be administered orally for treatment of hemoglobinopathies such as SCD. 2.
- the present disclosure provides 2-arylbenzimidazole compounds and pharmaceutical compositions or formulations for the treatment of hemoglobinopathies in a subject.
- the hemoglobinopathy is a sickle cell disease (SCD).
- SCD sickle cell disease
- the present disclosure also provides 2-arylbenzimidazole compounds and pharmaceutical compositions or formulations for increasing fetal hemoglobin (HbF) production in a subject.
- HbF fetal hemoglobin
- the present disclosure provides 2-arylbenzimidazole compounds (e.g., of formula (I), as described herein) and improved formulations of TQS-168 (e.g., comprising amorphous solid dispersions as described herein) for the treatment of hemoglobinopathies in a subject.
- 2-arylbenzimidazole compounds e.g., of formula (I), as described herein
- improved formulations of TQS-168 e.g., comprising amorphous solid dispersions as described herein
- HbF fetal hemoglobin
- TQS-168 (2-(4-tert-butylphenyl)-1H-benzimidazole), previously known as ZLN-005, is known to be an activator of Ppargc1 ⁇ (PGC-1 ⁇ ) expression (Zhang et al., Diabetes 62:1297- 1307 (2013)).
- PPC-1 ⁇ Ppargc1 ⁇
- TQS-168 has previously been shown to suppress myeloid-mediated inflammation and reduce disease severity in murine models of neurodegenerative diseases in which neuroinflammation contributes to the underlying pathophysiology, including Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS) (US Pat.
- TQS-168 has also been shown to suppress metabolic dysfunction in microglia in older mice, inhibit inflammatory cytokine production in microglia in older mice, suppress systemic inflammation in older mice, and alleviate behavioral dysfunction in older mice (US Pat. No.10,653,669, the disclosure of which is incorporated herein by reference in its entirety).
- TQS-168 and its analogs have also been shown to suppress acute systemic immune activation, including cytokine release syndrome (CRS) (WO2021/262617, the disclosure of which is incorporated herein by reference in its entirety).
- TQS-168 has also been shown to induce ⁇ - globin expression and fetal hemoglobin (HbF) production in sickle mice (Sun et al., Br J Haematol.197:97-109 (2022)). The effects on both myeloid cells and erythroid cells appear to occur through the increase of PGC-1a gene expression.
- a range of 2-arylbenzimidazole compounds e.g., of formula (I), as described herein
- TQS-168 2-(4-tert-butylphenyl)-1H-benzimidazole
- TQS-168 e.g., comprising amorphous solid dispersions as described herein
- 2-arylbenzimidazole compounds e.g., of formula (I), as described herein
- improved formulations of TQS-168 e.g., comprising amorphous solid dispersions as described herein for use in increasing fetal hemoglobin (HbF) production in a subject.
- a method of treating a hemoglobinopathy in a subject comprising administering to a subject suffering from a hemoglobinopathy an effective amount of a compound of formula (I): or a pharmaceutically acceptable salt, solvate, deuterated derivative, or prodrug
- W 1 is chosen from O, S, and N-R 1 , or, when W 9 is N, W 1 may additionally be C-R 50 ;
- W 2 is N or C-R 2 ;
- W 3 is N or C-R 3 ;
- W 4 is N or C-R 4 ;
- W 5 is N or C-R 5 ;
- W 6 is N or C-R 6 ;
- W 7 is N or C-R 7 ;
- W 8 is N or C-R 8 ;
- W 9 is C, or, when W 1 is C-R 50 ;
- W 9 may be N;
- a method of increasing fetal hemoglobin (HbF) production comprising administering to a subject in need of increased HbF production an effective amount of a compound of formula (I) (e.g., as described herein), or a pharmaceutically acceptable salt, a solvate, or prodrug thereof.
- a compound of formula (I) e.g., as described herein
- a pharmaceutically acceptable salt, a solvate, or prodrug thereof e.g., as described herein
- a method of treating a hemoglobinopathy comprising administering to a subject suffering from a hemoglobinopathy an effective amount of a pharmaceutical composition comprising: an amorphous solid dispersion of 2-(4-tert-butylphenyl)-1H-benzimidazole (TQS-168) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier matrix.
- a pharmaceutical composition comprising: an amorphous solid dispersion of 2-(4-tert-butylphenyl)-1H-benzimidazole (TQS-168) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier matrix.
- a method of increasing fetal hemoglobin (HbF) production comprising administering to a subject in need of increased HbF production an effective amount of a pharmaceutical composition comprising: an amorphous solid dispersion of 2-(4-tert-butylphenyl)-1H-benzimidazole (TQS-168) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier matrix.
- a pharmaceutical composition comprising: an amorphous solid dispersion of 2-(4-tert-butylphenyl)-1H-benzimidazole (TQS-168) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier matrix.
- TQS-168 2-(4-tert-butylphenyl)-1H-benzimidazole
- the hemoglobinopathy is a sickle cell disease.
- the sickle cell disease is sickle cell anemia (HbSS). 3. DETAILED DESCRIPTION 3.1.
- methods for treating a hemoglobinopathy comprise administering to a subject suffering from a hemoglobinopathy an effective amount of a compound of formula (I), as described hereinbelow, or a pharmaceutically acceptable salt, solvate, deuterated derivative, or prodrug thereof.
- a hemoglobinopathy comprises administering to a subject suffering from a hemoglobinopathy an effective amount of a compound of formula (I), as described hereinbelow, or a pharmaceutically acceptable salt, solvate, deuterated derivative, or prodrug thereof.
- further methods are provided for treating a hemoglobinopathy.
- the methods comprise administering to a subject suffering from a hemoglobinopathy an effective amount of a pharmaceutical composition comprising an amorphous solid dispersion of (2-(4-tert- butylphenyl)-1H-benzimidazole) (TQS-168), or a pharmaceutically acceptable salt, solvate, deuterated derivative, or prodrug thereof.
- a pharmaceutical composition comprising an amorphous solid dispersion of (2-(4-tert- butylphenyl)-1H-benzimidazole) (TQS-168), or a pharmaceutically acceptable salt, solvate, deuterated derivative, or prodrug thereof.
- the methods comprise administering to a subject in need of increased HbF production an effective amount of a pharmaceutical composition comprising an amorphous solid dispersion of (2-(4-tert- butylphenyl)-1H-benzimidazole) (TQS-168), or a pharmaceutically acceptable salt, solvate, deuterated derivative, or prodrug thereof.
- a pharmaceutical composition comprising an amorphous solid dispersion of (2-(4-tert- butylphenyl)-1H-benzimidazole) (TQS-168), or a pharmaceutically acceptable salt, solvate, deuterated derivative, or prodrug thereof.
- TQS-168 amorphous solid dispersion of (2-(4-tert- butylphenyl)-1H-benzimidazole)
- TQS-168 amorphous solid dispersion of (2-(4-tert- butylphenyl)-1H-benzimidazole)
- the patient has been diagnosed based on symptoms and on genotype.
- the hemoglobinopathy is a ⁇ -hemoglobinopathy.
- the hemoglobinopathy is a sickle cell disease (SCD), a sickle cell anemia, a sickle cell trait (SCT), or a ⁇ -thalassemia.
- the hemoglobinopathy is a ⁇ -thalassemia.
- the hemoglobinopathy is a sickle cell disease (SCD).
- the hemoglobinopathy is a sickle cell trait (SCT).
- the SCD is selected from sickle cell anemia (HbSS), sickle- hemoglobin C disease (HbSC), sickle beta-plus-thalassemia (HbS/ ⁇ +), and sickle beta-zero- thalassemia (HbS/ ⁇ O).
- HbSS sickle cell anemia
- HbSC sickle-hemoglobin C disease
- HbS/ ⁇ + sickle beta-plus-thalassemia
- HbS/ ⁇ O sickle beta-zero-thalassemia
- the subject is identified as suffering from a sickle cell crisis, or has been identified as being at risk of incurring a sickle cell crisis prior to treatment.
- the treatment according to the present method can ameliorate one or more symptoms associated with the hemoglobinopathy, such as anemia, tissue hypoxia, organ dysfunction, abnormal hematocrit values, ineffective erythropoiesis, abnormal reticulocyte (erythrocyte) count, abnormal iron load, the presence of ring sideroblasts, splenomegaly, hepatomegaly, impaired peripheral blood flow, dyspnea, increased hemolysis, jaundice, anemic pain crises, acute chest syndrome, splenic sequestration, priapism, stroke, hand-foot syndrome, and pain such as angina pectoris, by increasing the amount of fetal hemoglobin in the individual [0030]
- the method further comprises administering to the subject one or more additional active agents, including additional active agents described herein.
- HbF fetal hemoglobin
- the subject in need of increased HbF production has a hemoglobinopathy, including the hemoglobinopathies described in Section 3.1.1 herein.
- the subject in need of increased HbF production has sickle cell anemia.
- the subject in need of increased HbF production is heterozygous for sickle cell trait.
- the percentage of HbF production in the subject is increased by 1% or more, such as 2% or more, 3% or more, 4% or more, 5% or more, 6% or more, 7% or more, 8% or more, 9% or more, 10% or more, or even more, relative to a mean baseline level of HbF in RBCs in the subject before treatment according to the methods described herein.
- the percentage of HbF production in the subject is increased by 10% or more, such as 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, relative to a baseline level of HbF production in the subject before treatment according to the methods described herein.
- increasing HbF production in a subject means increasing the HbF production by a factor of 2 or more, such as 3 or more, 4 or more, 5 or more, 10 or more, 100 or more, or even more, relative to a baseline level of HbF production in the subject before treatment according to the methods described herein.
- the method further comprises administering to the subject one or more additional active agents, including those described herein below. 3.1.3. Subject Age [0034] In typical embodiments, the subject is a human patient. [0035] In some embodiments, the human patient is under the age of 1 year.
- the human patient is 2-5 years old, 5-10 years old, 10-15 years old, 15-20 years old, 20-25 years old, 25-30 years old, 30-35 years old, or 35-40 years of age. [0036] In some embodiments, the human is no more than 40 years of age. In some embodiments, the human is no more than 5 years of age. In some embodiments, the human is no more than 10 years of age. In some embodiments, the human is no more than 15 years of age. In some embodiments, the human is no more than 20 years of age. In some embodiments, the human is no more than 25 years of age. In some embodiments, the human is no more than 30 years of age.
- the human is no more than 40 years of age, such as no more than 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 years of age, or no more than 1 year of age. [0037] In some embodiments, the human is over 40 years of age. In some embodiments, the human is over 45 years of age. In some embodiments, the human is over 50 years of age. In some embodiments, the human is over 55 years of age. In some embodiments, the human is over 60 years of age. In some embodiments, the human is over 65 years of age. In some embodiments, the human is over 70 years of age.
- the human is over 75 years of age. In some embodiments, the human is over 80 years of age. In some embodiments, the human is over 85 years of age. In some embodiments, the human is over 90 years of age. [0038] In various embodiments, the human is 30 to 100 years of age, such as 30 to 40 years, 30 to 50 years, 30 to 60 years, 30 to 70 years, 30 to 80 years, 30 to 90 years, 40 to 50 years, 40 to 60 years, 40 to 70 years, 40 to 80 years, 40 to 90 years, 40 to 100 years, 50 to 60 years, 50 to 70 years, 50 to 80 years, 50 to 90 years, 50 to 100 years, 60 to 70 years, 60 to 80 years, 60 to 90 years, 60 to 100 years, 70 to 80 years, 70 to 90 years, 70 to 100 years, 80 to 90 years, 80 to 100 years, or 90 to 100 years of age.
- 30 to 100 years of age such as 30 to 40 years, 30 to 50 years, 30 to 60 years, 30 to 70 years, 30 to 80 years, 30 to 90 years, 40 to 50 years
- the methods of treating a hemoglobinopathy and/or for increasing production of HbF in a subject comprise administering a therapeutically effective amount of one or more compounds of formula (I), or a pharmaceutically acceptable salt, solvate, deuterated derivative, or prodrug thereof to the subject in need thereof, where Formula (I) is [0040]
- W 1 is N-R 1 and R 1 is hydrogen;
- W 1 is N-R 1 and R 1 is hydrogen
- W 2 is C-R 2 , wherein R 2 is selected from hydrogen, perfluoro(C 1 -C 4 )alkyl, (C 1 - C 4 )alkyl, (C 1 -C 4 )alkoxy, perfluoro(C 1 -C 4 )alkoxy, amino, hydroxy, nitrile, halo and carboxamide
- W 3 is C-R 3 , wherein R 3 is selected from hydrogen, perfluoro(C 1 -C 4 )alkyl, (C 1 - C 4 )alkyl, (C 1 -C 4 )alkoxy, perfluoro(C 1 -C 4 )alkoxy, amino, hydroxy, nitrile, halo and carboxamide
- W 4 is C-R 4 , wherein R 4 is selected from hydrogen, perfluoro(C 1 -C 4 )alkyl, (C 1 - C 4 )alky
- W 1 is N-R 1 and R 1 is hydrogen
- W 2 is selected from C-H, C-F, C-D, C-CF 3 , C-CH 3 , C-Cl, C-Br, C-OH, C-OCH 3 , C-NH 2 , C-CF 2 H, C-OCF 3 , C-OCF 2 H, C-CD 3 , and C-CONH 2
- W 3 is selected from N, C-H, C-NH2, C-F, C-CF3, C-D, C-OCH3, C-CN, C-OH, C- Cl, C-CH3, C-CF2H, C-OCF3, C-OCF2H, C-CD3, and C-Br
- W 4 is selected from N, C-H, C-NH 2 , C-F, C-CF 3 , C-D, C-OCH 3 , C-CN, C-OH,
- W 2 and W 5 are independently selected from C-H, C-F, C-D, C-CF2H, C-CD3, and C-CF3;
- W 3 is selected from N, C-H, C-NH2, C-F, C-CF3, C-CF2H, C-CD3, and C-D;
- W 4 is selected from N, C-H, C-NH 2 , C-F, C-CF 3 , C-CF 2 H, C-CD 3 , and C-D;
- W 7 is C-H;
- R 8 is selected from H, tert-butyl, amino, and methoxy; and
- R 9 is H or tert-butyl.
- W 2 , W 3 , W 4 and W 5 are C-D or C-F.
- one of W 2 , W 3 , W 4 and W 5 is C-D or C-F.
- two of W 2 , W 3 , W 4 and W 5 are C-D or C-F.
- three of W 2 , W 3 , W 4 and W 5 are C-D or C-F.
- all of W 2 , W 3 , W 4 and W 5 are C-D or C- F.
- W 2 , W 3 , W 4 and W 5 are C-R 2 , C-R 3 , C-R 4 and C- R 5 respectively, and one of R 2 , R 3 , R 4 and R 5 is perfluoro(C 1 -C 4 )alkyl, C 1 -C 4 )alkyl, (C 1 - C 4 )alkoxy, perfluoro(C 1 -C 4 )alkoxy, amino, hydroxy, nitrile, halo or carboxamide, and the remainder are hydrogen.
- W 3 or W 4 is N and the other, along with W 2 and W 5 , is C-H.
- W 2 , W 3 , W 4 , W 5 , W 6 , and W 7 are C-H.
- R 8 is t-butyl.
- W 2 and W 5 are C-R 2 and C-R 5 , respectively; and R 2 , R 3 , R 4 , and R 5 are independently selected from H, deuterium, halo, (C1-C3)alkoxy, perfluoro(C1-C3)alkoxy, nitrile, amino, hydroxyl, aminocarbonyl, (C1-C3)alkyl, and perfluoro(C 1 -C 3 )alkyl.
- W 1 is N-H or C-H
- W 2 and W 5 are independently selected from C-H, C-F, C-D, C-CF 3 , C-CH 3 , C-Cl, C-Br, C-OH, C-OCH 3 , C-NH 2 , C-CF 2 H, C-OCF 3 , C-OCF 2 H, C-CD 3 , and C-CONH 2
- W 3 is selected from N, C-H, C-NH2, C-F, C-CF3, C-D, C-OCH3, C-CN, C-OH, C-Cl, C- CH3, C-CF2H, C-OCF3, C-OCF2H, C-CD3, and C-Br
- W 4 is selected from N, C-H, C-NH 2 , C-F, C-CF 3 , C-D, C-OCH 3 , C-CN, C-OH,
- W 2 and W 5 are independently selected from C-H, C-F, C-D, C-CF 2 H, C-CD 3 , and C-CF 3 ;
- W 3 is selected from N, C-H, C-NH 2 , C-F, C-CF 3 , C-CF 2 H, C-CD 3 , and C-D;
- W 4 is selected from N, C-H, C-NH2, C-F, C-CF3, C-CF2H, C-CD3, and C-D.
- W 3 or W 4 is N and the other, along with W 2 and W 5 , is C-H.
- W 2 , W 3 , W 4 , and W 5 are C-H.
- the compound may be of formula (I), (II), (III), or (IVA)-(IVE) unless otherwise indicated.
- W 1 is N-R 1 .
- W 1 is O. In yet other embodiments of formulae (I), (II) and (IVA)-(IVE), W 1 is S. In still other embodiments of formulae (I), (II) and (IVA)-(IVE), W 1 is C-R 50 , such as when W 9 is N. In some embodiments where W 1 is C-R 50 , R 50 is H. In other embodiments where W 1 is C-R 50 , R 50 is (C 1 -C 3 )alkyl.
- R 30 is chosen from: (a) (C 1 -C 6 )alkyl; (b) phenyl substituted with (C 1 -C 4 )alkylamino; (c) the descarboxy residue of a natural amino acid; (d) (C1-C3)hydrocarbyl substituted with carboxyl; (e) (C1-C5)oxaalkyl; and (d) pyridyl.
- R 1 is H.
- R 1 is (C 1 -C 3 )alkyl.
- W 2 is N.
- W 2 is C-R 2 .
- W 2 is chosen from C-H, C-F, C-D, C-CF 3 , C-CH 3 , C-Cl, C-Br, C-OH, C-OCH 3 , C-NH 2 , C-CF 2 H, C- OCF3, C-OCF2H, C-CD3, and C-CONH2, In some embodiments, W 2 is chosen from C-H, C-F, C-D, C-CF2H, C-CD3, and C-CF3.
- R 2 is chosen from hydrogen, perfluoro(C1- C4)alkyl, (C1-C4)alkyl, (C1-C4)alkoxy, perfluoro(C1-C4)alkoxy, amino, hydroxy, nitrile, halo or carboxamide.
- R 2 is chosen from hydrogen, trifluoromethyl, methyl, ethyl, methoxy, trifluoromethoxy, amino, hydroxy, nitrile, halo or carboxamide.
- R 2 is chosen from hydrogen, halo, and perfluoro(C1-C3)alkyl.
- W 3 is N. In other embodiments of formulae (I), (II), (III), and (IVA)-(IVE), W 3 is C-R 3 . In some embodiments, W 3 is chosen from N, C-H, C-NH2, C-F, C-CF3, C-D, C-OCH3, C-CN, C-OH, C-Cl, C-CH3, C- CF2H, C-OCF3, C-OCF2H, C-CD3, and C-Br.
- W 3 is chosen from N, C-H, C-NH 2 , C-F, C-CF 3 , C-CF 2 H, C-CD 3 , and C-D.
- R 3 is chosen from hydrogen, perfluoro(C1- C 4 )alkyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, perfluoro(C 1 -C 4 )alkoxy, amino, hydroxy, nitrile, halo or carboxamide.
- R 3 is chosen from hydrogen, trifluoromethyl, methyl, ethyl, methoxy, trifluoromethoxy, amino, hydroxy, nitrile, halo or carboxamide.
- W 3 is C-R 3
- R 3 is chosen from H, halo, and perfluoro(C 1 -C 3 )alkyl.
- W 4 is N.
- W 4 is C-R 4 .
- W 4 is chosen from N, C-H, C-NH 2 , C-F, C-CF 3 , C-D, C-OCH 3 , C-CN, C-OH, C-Cl, C-CH 3 , C- CF 2 H, C-OCF 3 , C-OCF 2 H, C-CD 3 , and C-Br. In some embodiments, W 4 is chosen from N, C-H, C-NH2, C-F, C-CF3, C-CF2H, C-CD3, and C-D.
- R 4 is chosen from hydrogen, perfluoro(C1- C4)alkyl, (C1-C4)alkyl, (C1-C4)alkoxy, perfluoro(C1-C4)alkoxy, amino, hydroxy, nitrile, halo or carboxamide.
- R 4 is chosen from hydrogen, trifluoromethyl, methyl, ethyl, methoxy, trifluoromethoxy, amino, hydroxy, nitrile, halo or carboxamide.
- W 4 is C-R 4
- R 4 is chosen from H, halo, and perfluoro(C 1 -C 3 )alkyl.
- W 5 is N.
- W 5 is C-R 5 .
- W 5 is chosen from C-H, C-F, C-D, C-CF 3 , C-CH 3 , C-Cl, C-Br, C-OH, C-OCH 3 , C-NH 2 , C-CF 2 H, C- OCF 3 , C-OCF 2 H, C-CD 3 , and C-CONH 2 .
- W 5 is chosen from C-H, C-F, C-D, C-CF2H, C-CD3, and C-CF3.
- R 5 is chosen from hydrogen, perfluoro(C1- C 4 )alkyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, perfluoro(C 1 -C 4 )alkoxy, amino, hydroxy, nitrile, halo or carboxamide.
- R 5 is chosen from hydrogen, trifluoromethyl, methyl, ethyl, methoxy, trifluoromethoxy, amino, hydroxy, nitrile, halo or carboxamide.
- R 5 is chosen from hydrogen, halo, and perfluoro(C 1 -C 3 )alkyl.
- W 6 is N. In other embodiments of formulae (II) and (III), W 6 is C-R 6 , such as C-H. [0078] In some embodiments where W 6 is C-R 6 , R 6 is chosen from hydrogen, deuterium, halo, (C 1 -C 3 )alkyl, perfluoro(C 1 -C 3 )alkyl, hydroxy, (C 1 -C 3 )alkoxy, perfluoro(C 1 -C 3 )alkoxy, and amino. [0079] In some embodiments of formulae (II) and (III), W 7 is N.
- W 7 is C-R 7 .
- R 7 is chosen from hydrogen, deuterium, hydroxy, cyano, amino, halogen, halo(C1-C4)alkyl, (C1-C4)alkyl, (C1- C4)alkoxy, and halo(C1-C4)alkoxy.
- W 7 is C-R 7
- R 7 is hydrogen or (C 3 -C 4 )alkyl.
- W 8 is N.
- W 8 is C-R 8 .
- R 8 is chosen from hydrogen, deuterium, halogen, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 - C 4 )alkoxy, cyano, phenyl, phenoxy, benzyloxy, and amino.
- R 8 is chosen from H, (C1-C4)alkyl, amino, (C1-C4)alkoxy, halo(C1-C4)alkoxy, and hydroxy.
- R 8 is chosen from H, tert-butyl, amino, and methoxy. In some embodiments R 8 is tert-butyl when W 7 is N or R 7 is hydrogen. [0081] In some embodiments of formulae (I), (III), and (IVA)-(IVE) when W 1 is CR 50 , W 9 is N. In other embodiments of formulae (I), (III), and (IVA)-(IVE) when W 1 is NR 1 , O, or S, W 9 is C.
- R 9 is chosen from hydrogen, deuterium, hydroxy, cyano, amino, halogen, halo(C1-C4)alkyl, (C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1- C4)alkoxy.
- R 7 is hydrogen and R 8 is H
- R 9 is tert-butyl.
- R 10 is chosen from hydrogen, deuterium, halo, (C 1 -C 3 )alkyl, perfluoro(C 1 -C 3 )alkyl, hydroxy, (C 1 -C 3 )alkoxy, perfluoro(C 1 -C 3 )alkoxy, and amino. In some embodiments, R 10 is hydrogen. [0084] In some embodiments of formula (I), Ar is . In some embodiments of formula (I), Ar is In some embodiments of formula (I), Ar is In some embodiments of formula (I), Ar is In some embodiments of formula (I), Ar is . [0085] In some embodiments, the compound of formula (I) is selected from a compound of Table 1:
- the compound is selected from 2-(4-(tert- Butyl)phenyl)-1H-imidazo[4,5-c]pyridine; 2-(4-tert-Butylphenyl)-1,3-benzothiazole; 2-(4-tert- Butylphenyl)-1,3-benzoxazole; 2-(4-tert-Butylphenyl)imidazo[1,2-a]pyridine; 2-(2- Chlorophenyl)-1H-benzo[d]imidazole; 2-(4-Chlorophenyl)-1H-benzo[d]imidazole; 2-(3- Methylphenyl)-1H-benzo[d]imidazole; 2-(6-tert-Butyl-3-pyridyl)-1H-benzo[d]imidazole; 2-(4- Methylphenyl)-1H-benzo[d]imidazole; 2-(2-Methyl
- the compound of formula (I) is 2-(4-tert-butylphenyl)-1H- benzo[d]imidazol-5-ol (Compound 26) having the formula: or a pharmaceutically acceptable salt, solvate, deuterated derivative, or prodrug, thereof.
- pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. When the compounds of the present disclosure are basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
- Suitable pharmaceutically acceptable acid addition salts for the compounds of the present disclosure include acetic, adipic, alginic, ascorbic, aspartic, benzenesulfonic (besylate), benzoic, boric, butyric, camphoric, camphorsulfonic, carbonic, citric, ethanedisulfonic, ethanesulfonic, ethylenediaminetetraacetic, formic, fumaric, glucoheptonic, gluconic, glutamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, laurylsulfonic, maleic, malic, mandelic, methanesulfonic, mucic, naphthylenesulfonic, nitric, oleic, pamoic, pantothenic, phosphoric, pivalic, polygalacturonic, salicylic, stearic, succin
- suitable pharmaceutically acceptable base addition salts for the compounds of the present disclosure include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, arginine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
- Further pharmaceutically acceptable salt, solvate, deuterated derivative, or prodrugs include, when appropriate, nontoxic ammonium cations and carboxylate, sulfonate and phosphonate anions attached to alkyl having from 1 to 20 carbon atoms.
- the compounds of formulae (I), (II), (III) and (IVA)-(IVE) may be administered as the raw chemical, in preferred embodiments they are presented as a pharmaceutical composition.
- the methods of the present disclosure include administration of a pharmaceutical composition comprising a compound of formula (I), (II), (III) and (IVA)-(IVE), or a pharmaceutically acceptable salt, solvate, deuterated derivative, or prodrug thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients.
- the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- the formulations of compounds of formulae (I), (II), (III) and (IVA)-(IVE) include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration.
- parenteral including subcutaneous, intradermal, intramuscular, intravenous and intraarticular
- topical including dermal, buccal, sublingual and intraocular
- the most suitable route may depend upon the condition and disorder of the recipient.
- the compound is formulated for oral administration.
- the formulations may conveniently be presented in unit dosage form (e.g., as described herein) and may be prepared by any of the methods well known in the art of pharmacy.
- All methods include the step of bringing into association a compound of formula (I), (II), (III) and (IVA)-(IVE), or a pharmaceutically acceptable salt, solvate, deuterated derivative, or prodrug thereof ("active ingredient"), with the carrier which constitutes one or more accessory ingredients.
- active ingredient a pharmaceutically acceptable salt, solvate, deuterated derivative, or prodrug thereof.
- the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
- Formulations of the present disclosure suitable for oral administration may be presented as discrete units such as capsules, tablets or sachets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
- the active ingredient may also be presented as a bolus, electuary or paste.
- Amorphous solid dispersions of 2-(4-tert-butylphenyl)-1H-benzimidazole (TQS-168) [0092]
- the methods of treating a hemoglobinopathy and/or for increasing production of HbF in a subject comprise administering a therapeutically effective amount of 2-(4-tert-butylphenyl)-1H-benzimidazole (TQS-168; also known as ZLN-005), or a pharmaceutically acceptable salt, solvate, deuterated derivative, or prodrug thereof, in an amorphous solid dispersion.
- a solid dispersion refers to a system in a solid-state comprising at least two components, wherein one component (e.g., a drug substance) is dispersed throughout the other component or components.
- solid dispersions of TQS-168 of the present application comprises TQS-168 or a pharmaceutically acceptable salt, solvate, deuterated derivative, or prodrug, and a pharmaceutically acceptable carrier matrix.
- the solid dispersions of TQS-168 may be formed by any conventional technique, e.g., spray drying, co-grinding, hot melt extrusion, freeze drying, rotary evaporation, solvent evaporation, co-precipitation, lyophilization, or any suitable solvent removal process.
- the amorphous solid dispersion is prepared by spray drying (e.g., to obtain a spray-dried dispersion (SDD) formulation of TQS-168).
- the amorphous solid dispersion is prepared by hot-melt extrusion (e.g., to obtain a hot-melt extrusion (HME) formulation of TQS-168).
- the TQS-168 starting material used in the process for preparation of the solid dispersion may be crystalline or amorphous form. Alternatively, it may be obtained in situ from a previous processing step.
- TQS-168 in the solid dispersion obtained is present in an amorphous form.
- a solid that is in the “amorphous” solid state form means that it is in a non-crystalline state.
- Amorphous solids generally possess crystal-like short-range molecular arrangement, but no long-range order of molecular packing as are found in crystalline solids.
- the solid-state form of a solid, such as the drug substance in the amorphous dispersion may be determined by Polarized Light Microscopy, X-Ray Powder Diffraction (XPRD), Differential Scanning calorimetry (DSC), or other standard techniques known to those of skill in the art.
- the amorphous solid contains TQS-168 in a substantially amorphous solid-state form, e.g., at least about 80% of TQS-168 in the dispersion is in an amorphous form, such as at least about 90% of TQS-168 in the dispersion is in an amorphous form, or at least about 95% of TQS-168 in the dispersion is in amorphous form.
- At least about 90% e.g., at least 95%, 96%, 97%, 98%, 99%, 99.5%, or even 99.9%, such as from 90% to 99.9%, from 90% to 99.5%, from 90% to 99%, from 90% to 98%, from 90% to 97%, from 90% to 96%, from 90% to 95%, from 95% to 99.9%, from 95% to 99.5%, from 95% to 99%, from 95% to 98%, from 95% to 97%, and from 95% to 96%) of TQS-168 is in amorphous form.
- the solid dispersion can be in a single phase such as substitutional or interstitial amorphous solutions; or it can be a two-phase system such as eutectics, amorphous drug and amorphous carrier dispersions. Solid solutions are a resultant single phase upon dispersion of two compounds in each other, at their molecular level.
- the amorphous solid dispersion of TQS-168 includes at least one pharmaceutically acceptable carrier in the carrier matrix.
- the carrier matrix comprises a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (e.g., soluplus), a polyvinylpyrrolidone polymer (e.g., PVP K30), a copovidone polymer (e.g., PVP VA64 or Kollidon VA64), a povidone polymer (e.g., Kollidon 17PF), a hydroxypropyl methyl cellulose polymer (e.g., HPMC AS), a dimethylaminoethyl methacrylate-copolymer (e.g., Eudragit EPO), a methacrylic acid-methyl methacrylate copolymer (e.g., Eudragit L100), a polyethylene glycol polymer (e.g., PEG 8000), amorphous silicon dioxide (e.g., Syloid® 244 FP) and mixtures thereof
- the hydroxypropyl methylcellulose acetate succinate comprises various types, such as LF, LG, MF, MG, HF and HG, etc.
- L, M and H of the type's names mean the pH level at the beginning of dissolution of HPMC-AS.
- L refers to low level (e.g., HPMC-AS begins to be dissolved when the pH value is more than 5.5)
- M refers to middle level (e.g., HPMC-AS begins to be dissolved when the pH value is more than 6.0)
- H refers to high level (e.g., HPMC-AS begins to be dissolved when the pH value is more than 6.5).
- the second letters F and G refer to the particle size of HPMC-AS, where F refers to fine powder, and G refers to granular.
- the type of HPMC-AS is LF; in some embodiments, the type of HPMC-AS is MF; in some embodiments, the type of HPMC-AS is HG.
- any convenient carrier polymer can find use in subject amorphous solid dispersion formulations.
- the carrier polymers include but are not limited to, cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate, methyl cellulose phthalate, ethylhydroxymethylcellulose phthalate, hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose acetate maleate, hydroxypropylmethylcellulose trimellitate, carboxymethylethyl cellulose, polyvinyl butyrate phthalate, polyvinyl acetate phthalate, a methacrylic acid/ethyl acrylate copolymer and a methacrylic acid/methyl methacrylate copolymer.
- the polymer is selected from HPMCP, HPMC-AS, hydroxypropylmethyl cellulose acetate maleate and hydroxypropylmethylcellulose trimellitate.
- the carrier polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinylpyrrolidone (povidone), poly(vinylpyrrolidone/vinylacetate) (copovidone), polyvinylcaprolactam/polyvinylacetate/polyethylene glycol graft copolymer, polyethylene glycol/polyvinyl alcohol graft copolymer, polyethylene oxide, polypropylene oxide, copolymers of ethylene oxide and propylene oxide, polyvinyl alcohol, partially saponified polyvinylalcohol, macrogolglycerol hydroxystearate, polyethylene glycol, and maltodextrins.
- the carrier polymer is a copovidone polymer.
- the carrier matrix comprises a copovidone polymer, a povidone polymer, a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, amorphous silicon dioxide (e.g., Syloid® 244 FP), or a mixture thereof.
- carrier matrix comprises a mixture of a polyvinyl caprolactam- polyvinyl acetate-polyethylene glycol graft co-polymer (e.g., soluplus), and amorphous silicon dioxide (e.g., Syloid® 244 FP).
- carrier matrix comprises a mixture of copovidone polymer, a povidone polymer, and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co- polymer.
- the amorphous solid dispersion of the TQS-168, and pharmaceutically acceptable carrier matrix have a weight ratio of the TQS-168 to the carrier matrix of from 1:6 to 1:1 (e.g., from 1:6 to 1:2, from 1:6 to 1:2.5, from 1:6 to 1:3, from 1:6 to 1:3.5, from 1:6 to 1:4, from 1:6 to 1:4.5, from 1:6 to 1:5, from 1:5 to 1:2, from 1:5 to 1:2.5, from 1:5 to 1:3, from 1:5 to 1:3.5, from 1:5 to 1:4, from 1:5 to 1:4.5, from 1:5 to 1:1.5, from 1:4 to 1:1.5, from 1:4 to 1:2, from 1:4 to 1:2.5, from 1:4 to 1:3, from 1:4 to 1:3.5, from 1:3 to 1:1.5, from 1:3 to 1:2, from 1:3 to 1:2.5, and from 1:2 to 1:1.5).
- 1:6 to 1:1 e.g.,
- TQS-168 and carrier matrix are present in a ratio of from 1:1 to 1:6 (w/w), 1:1 to 1:4 (w/w), such as in the ratio of 1:2 to 1.3 (w/w).
- Solid dispersions of the present disclosure optionally may include one or more solubilizers, i.e., additives which increase solubility of the pharmaceutical active ingredient in the solid dispersion or additives which act as pore-forming agents in the solid dispersion.
- Suitable solubilizers for use in compositions of the present disclosure include mannitol, transcutol, polyvinylalcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone, glycofurol and transcutol.
- concentration of solubilizer ranges from about 0.5% to about 30% w/w of carrier concentration.
- the amorphous solid dispersions of the present disclosure optionally may include one or more surfactants.
- Surfactants are compounds which are capable of improving the wetting of the pharmaceutical active ingredient and/or enhancing the dissolution.
- the surfactants can be selected from hydrophilic surfactants or lipophilic surfactants or mixtures thereof.
- the surfactants can be anionic, nonionic, cationic, and zwitterionic surfactants.
- Surfactants according to the present disclosure include, but not limited to, polyoxyethylene alkylaryl ethers such as polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether; polyethylene glycol fatty acid esters such as PEG monolaurate, PEG dilaurate, PEG distearate, PEG dioleate; polyoxyethylene sorbitan fatty acid ester such as polysorbate 40, polysorbate 60, polysorbate 80; sorbitan fatty acid mono esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, sodium lauryl sulfate, sodium dioctyl sulfosuccinate (DOSS), lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene
- the concentration of surfactant ranges from about 0.1% to about 10% w/w of carrier concentration.
- the percentage loading of TQS-168 in the solid dispersion is from 1% to 40% (w/w) (e.g., from 1% to 35%, from 10% to 35%, from 10% to 30%, from 20% to 30%, from 21% to 30%, from 22% to 30%, from 23% to 30%, from 24% to 30%, from 25% to 30%, from 26% to 30%, from 27% to 30%, from 28% to 30%).
- the percentage loading of TQS-168 is from 15% to 35% (w/w) (e.g., from 15% to 34%, from 15% to 33%, from 15% to 32%, from 15% to 31%, from 15% to 30%, from 20% to 30%, from 20% to 25%, from 25% to 30%). [0113] In some embodiments, the percentage loading of TQS-168 in the solid dispersion is from 20-30 % w/w. In some embodiments, the percentage loading of TQS-168 in the solid dispersion is from 25-30% w/w, such as 25%, 26%, 27%, 28%, 29%, or 30% w/w TQS-168.
- the percentage loading of TQS-168 in the solid dispersion is 25% w/w. In some embodiments, the percentage loading of TQS-168 in the solid dispersion is 30% w/w. [0114] In some embodiments herein, the percentage loading of TQS-168 in the solid dispersion is from 1% to 40% (w/w) (e.g., from 1% to 35%, from 10% to 35%, from 10% to 30%, from 20% to 30%, from 21% to 30%, from 22% to 30%, from 23% to 30%, from 24% to 30%, from 25% to 30%, from 26% to 30%, from 27% to 30%, from 28% to 30%, from 30% to 40%, from 35% to 40%).
- w/w e.g., from 1% to 35%, from 10% to 35%, from 10% to 30%, from 20% to 30%, from 21% to 30%, from 22% to 30%, from 23% to 30%, from 24% to 30%, from 25% to 30%, from 26% to 30%, from 27% to 30%, from 28% to 30%
- the percentage loading of TQS-168 is from 15% to 35% (w/w) (e.g., from 15% to 34%, from 15% to 33%, from 15% to 32%, from 15% to 31%, from 15% to 30%, from 20% to 30%, from 20% to 25%, from 25% to 30%).
- the percentage of the pharmaceutically acceptable carrier matrix in the solid dispersion is from 1% to 90% (w/w) (e.g., from 1% to 19%, from 10% to 19%, from 10% to 20%, from 10% to 30%, from 10% to 40%, from 10% to 50%, from 10% to 60%, from 10% to 70%, from 10% to 80%, from 10% to 90%, from 20% to 30%, from 20% to 40%, from 20% to 50%, from 20% to 60%, from 20% to 70%, from 20% to 80%, from 20% to 90%, from 21% to 30%, from 21% to 34%, from 21% to 40%, from 21% to 50%, from 21% to 60%, from 21% to 70%, from 21% to 80%, from 21% to 90%, from 30% to 40%, from 30% to 50%, from 30% to 60%, from 30% to 70%, from 30% to 80%, from 30% to 90%, from 36% to 40%, from 36% to 49%, from 36% to 60%, from 36% to 70%, from 36% to 80%, from 36% to 90%, from 40% to 50%, 1% to 90%, from 40% to
- the percentage of the pharmaceutically acceptable carrier matrix in the solid dispersion is from 60% to 85% (w/w) (e.g., from 60% to 80%, from 60% to 75%, from 60% to 70%, from 65% to 85%, from 65% to 80%, from 65% to 80%, from 65% to 77%, from 65% to 76%, from 65% to 75%, from 66% to 75%, from 66% to 75%, from 67% to 75%, from 68% to 75%, and from 70% to 75%).
- the percentage of the pharmaceutically acceptable carrier matrix in the solid dispersion is from 60% to 85% (w/w) (e.g., from 65% to 80%, from 65% to 75%, and from 70 to 75).
- the percentage of the pharmaceutically acceptable carrier matrix in the solid dispersion is from 65% to 80% (w/w). In some embodiments, the percentage of the pharmaceutically acceptable carrier matrix in the solid dispersion is 70% (w/w). In some embodiments, the percentage of the pharmaceutically acceptable carrier matrix in the solid dispersion is 75% (w/w).
- amorphous solid dispersions of TQS-168 are obtained by a spray drying process. Spray dried dispersions are obtained by dissolving drug and the carrier polymer in an organic solvent and then spray-drying the mixture to obtain a spray-dried dispersion (SDD).
- an amorphous solid dispersion comprising TQS-168 and a pharmaceutically acceptable carrier matrix, wherein the amorphous solid dispersion is prepared by spray-drying (e.g., to obtain a spray-dried dispersion (SDD) formulation).
- SDD spray-dried dispersion
- a spray-dried dispersion comprising 10-30% w/w of TQS-168 and 70-90% of a pharmaceutically acceptable carrier matrix, wherein the amorphous solid dispersion is prepared by spray-drying (e.g., to obtain a spray-dried dispersion (SDD) formulation).
- spray-drying e.g., to obtain a spray-dried dispersion (SDD) formulation.
- SDD spray dried dispersion
- SDD is a single phase amorphous molecular dispersion of a drug in a polymer matrix. It is a solid solution prepared by dissolving the drug and a polymer in a solvent (e.g., methanol, 2-propanol or the like) and spray drying the solution.
- a spray-dried dispersion (SDD) formulation comprising TQS-168 and a pharmaceutically acceptable carrier matrix.
- a spray-dried dispersion comprising 10-30% w/w of TQS-168 and 70-90% of a pharmaceutically acceptable carrier matrix.
- the percentage loading of TQS-168 in the spray-dried dispersion (SDD) formulation is from 15-40 % w/w.
- the percentage loading of TQS-168 in the spray-dried dispersion (SDD) formulation is from 20-40% w/w, such as 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, or 40% w/w TQS-168. In some embodiments, the percentage loading of TQS- 168 in the spray-dried dispersion (SDD) formulation is 30% w/w.
- the percentage of the pharmaceutically acceptable carrier matrix in the spray-dried dispersion (SDD) formulation is from 60% to 85% (w/w) (e.g., from 70% to 80%, and from 70% to 75%). In some embodiments, the percentage of the pharmaceutically acceptable carrier matrix in the spray-dried dispersion (SDD) formulation is from 70% to 75% (w/w), such as 70%, 71%, 72%, 73%, 74%, or 75% (w/w). In some embodiments, the percentage of the pharmaceutically acceptable carrier matrix in the solid dispersion is 70% (w/w).
- the pharmaceutically acceptable carrier matrix comprises a polyvinyl caprolactam-polyvinyl acetate- polyethylene glycol graft co-polymer (e.g., soluplus), a polyvinylpyrrolidone polymer (e.g., PVP K30), a copovidone polymer (e.g., PVP VA64 or Kollidon VA64), a povidone polymer (e.g., Kollidon 17PF), a hydroxypropyl methyl cellulose polymer (e.g., HPMC AS), a dimethylaminoethyl methacrylate-copolymer (e.g., Eudragit EPO), a methacrylic acid-methyl methacrylate copolymer (e.g., Eudragit L100), a polyethylene glycol polymer (e.g., PEG 8000), amorphous silicon dioxide (e.g.,
- the pharmaceutically acceptable carrier matrix comprises a polyvinyl caprolactam-polyvinyl acetate- polyethylene glycol graft co-polymer (e.g., soluplus), and amorphous silicon dioxide (e.g., Syloid® 244 FP).
- the ratio of amorphous silicon dioxide (e.g., Syloid® 244 FP) to polyvinyl caprolactam-polyvinyl acetate- polyethylene glycol graft co-polymer (e.g., soluplus) is from 1:2 to 1:1 (e.g., from 1:2 to 1:1.1, from 1:2 to 1:1.2, from 1.2 to 1:1.3, from 1:2 to 1:1.4, from 1:2 to 1:1.5, from 1:2 to 1:1.6, from 1:2 to 1:1.7, from 1:2 to 1:1.8, from 1:2 to 1:1.9, from 1:1.9 to 1:1, from 1:1.8 to 1:1, from 1:1.7 to 1:1, from 1:1.6 to 1:1, from 1:1.5 to 1:1, from 1:1.6 to 1:1, from 1:1.5 to 1:1, from 1:1.4 to 1:1, from 1:1.3 to 1:1, from 1:1.2 to 1:1, and from 1:1.1 to 1:1).
- amorphous silicon dioxide e.g., Syloid® 244 FP
- the ratio of amorphous silicon dioxide (e.g., Syloid® 244 FP) to polyvinyl caprolactam-polyvinyl acetate- polyethylene glycol graft co-polymer (e.g., soluplus) is 1:1.3.
- the amorphous solid dispersion of the TQS-168, and pharmaceutically acceptable carrier matrix have a weight ratio of the TQS-168 to the carrier matrix of from 1:6 to 1:1 (e.g., from 1:6 to 1:2, from 1:6 to 1:2.5, from 1:6 to 1:3, from 1:6 to 1:3.5, from 1:6 to 1:4, from 1:6 to 1:4.5, from 1:6 to 1:5, from 1:5 to 1:2, from 1:5 to 1:2.5, from 1:5 to 1:3, from 1:5 to 1:3.5, from 1:5 to 1:4, from 1:5 to 1:4.5, from 1:5 to 1:1.5, from 1:4 to 1:1.5, from 1:4 to 1:2, from 1:4 to 1:2.5, from 1:4 to 1:3, from 1:4 to 1:3.5, from 1:3 to 1:1.5, from 1:3 to 1:2, from 1:3 to 1:2.5
- TQS-168 and carrier matrix are present in a ratio of from 1:1 to 1:6 (w/w), 1:1 to 1:4 (w/w), such as in the ratio of 1:2 to 1.3 (w/w).
- amorphous solid dispersions of TQS-168 are obtained by hot melt extrusion.
- hot-melt extrusion or hot-melt extruded is used herein to describe a process whereby a composition is heated and/or compressed to a molten (or softened) state and subsequently forced through an orifice in a die where the extruded product is formed into its final shape in which it solidifies upon cooling.
- the blend is conveyed through one or more heating zones typically by a screw mechanism.
- the screw or screws are rotated by a variable speed motor inside a cylindrical barrel where only a small gap exists between the outside diameter of the screw and the inside diameter of the barrel. In this conformation, high shear is created at the barrel wall and between the screw fights by which the various components of the powder blend are well mixed and disaggregated.
- the die can be a dual manifold, multi-manifold or feed-block style die.
- an amorphous solid dispersion comprising TQS- 168 and a pharmaceutically acceptable carrier matrix, wherein the amorphous solid dispersion is prepared by hot-melt extrusion (e.g., to obtain a hot-melt extrusion (HME) formulation).
- a spray-dried dispersion comprising 10-30% w/w of TQS-168 and 70-90% of a pharmaceutically acceptable carrier matrix, wherein the amorphous solid dispersion is prepared by hot-melt extrusion (e.g., to obtain a hot-melt extrusion (HME) formulation).
- a hot-melt extrusion (HME) formulation comprising TQS-168 and a pharmaceutically acceptable carrier matrix.
- a hot-melt extrusion formulation comprising 10-30% w/w of TQS- 168 and 70-90% of a pharmaceutically acceptable carrier matrix.
- the percentage loading of TQS-168 in the hot-melt extrusion (HME) formulation is from 15-30 % w/w.
- the percentage loading of TQS-168 in the hot-melt extrusion (HME) formulation is from 20-40% w/w, such as 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, or 40% w/w TQS-168. In some embodiments, the percentage loading of TQS-168 in hot-melt extrusion (HME) formulation is 25% w/w.
- the percentage of the pharmaceutically acceptable carrier matrix in the hot-melt extrusion (HME) formulation is from 60% to 85% (w/w) (e.g., from 70% to 80%, and from 70% to 75%). In some embodiments, the percentage of the pharmaceutically acceptable carrier matrix in the hot-melt extrusion (HME) formulation is from 70% to 75% (w/w), such as 70%, 71%, 72%, 73%, 74%, or 75%. In some embodiments, the percentage of the pharmaceutically acceptable carrier matrix in the hot-melt extrusion (HME) formulation is 75% (w/w).
- the pharmaceutically acceptable carrier matrix comprises a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (e.g., soluplus), a polyvinylpyrrolidone polymer (e.g., PVP K30), a copovidone polymer (e.g., PVP VA64 or Kollidon VA64), a povidone polymer (e.g., Kollidon 17PF), a hydroxypropyl methyl cellulose polymer (e.g., HPMC AS), a dimethylaminoethyl methacrylate-copolymer (e.g., Eudragit EPO), a methacrylic acid-methyl methacrylate copolymer (e.g., Eudragit L100), a polyethylene glycol polymer (e.g., PEG 8000), amorphous silicon dioxide (e.g.
- the pharmaceutically acceptable carrier matrix comprises a mixture of copovidone polymer, a povidone polymer, and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer.
- the ratio of copovidone polymer, a povidone polymer, and a polyvinyl caprolactam-polyvinyl acetate- polyethylene glycol graft co-polymer is 1:1:1.
- the amorphous solid dispersion of the TQS-168, and pharmaceutically acceptable carrier matrix have a weight ratio of the TQS-168 to the carrier matrix of from 1:6 to 1:1 (e.g., from 1:6 to 1:2, from 1:6 to 1:2.5, from 1:6 to 1:3, from 1:6 to 1:3.5, from 1:6 to 1:4, from 1:6 to 1:4.5, from 1:6 to 1:5, from 1:5 to 1:2, from 1:5 to 1:2.5, from 1:5 to 1:3, from 1:5 to 1:3.5, from 1:5 to 1:4, from 1:5 to 1:4.5, from 1:5 to 1:1.5, from 1:4 to 1:1.5, from 1:4 to 1:2, from 1:4 to 1:2.5, from 1:4 to 1:3, from 1:4 to 1:3.5, from 1:3 to 1:1.5, from 1:3 to 1:2, from 1:3 to 1:2.5
- TQS-168 and carrier matrix are present in a ratio of from 1:1 to 1:6 (w/w), 1:1 to 1:4 (w/w), such as in the ratio of 1:2 to 1.3 (w/w).
- pharmaceutical compositions [0137]
- the subject compounds – e.g., compounds of formula (I) and subject amorphous solid dispersions comprising TQS-168 – are formulated in pharmaceutical compositions together with one or more pharmaceutically acceptable excipients.
- the subject compounds and amorphous solid dispersion may be blended with any one of the excipients described herein (e.g., to form a blended powder or granules) or for filling any one of the dosage forms described herein (e.g., tableting).
- the compounds and amorphous solid dispersion can optionally be further processed before blending or filling. Exemplary further processing includes spheronizing, pelletizing, milling, injection molding, sieving, and/or calendering.
- Compounds and amorphous solid dispersions of the present disclosure can be optionally subjected to a particle size reduction procedure before or after the completion of drying of the product to produce desired particle sizes and distributions.
- Milling or micronization can be performed to achieve the desired particle sizes or distributions.
- Equipment that may be used for particle size reduction include, without limitation thereto, ball mills, roller mills, hammer mills, and jet mills.
- the compounds and amorphous solid dispersion may be combined with pharmaceutically acceptable excipients to make other pharmaceutical compositions, or a finished dosage form (e.g., as described herein).
- the one or more additional pharmaceutically acceptable excipients are selected from diluents, binders, disintegrants, lubricants, glidants, surfactants, solubilizers, plasticizers, stabilizing agents, antioxidants, sweeteners, colors, flavors, preservatives, and combinations thereof.
- Other pharmaceutically acceptable excipients may include, but are not limited to, diluents, binders, disintegrating agents, surfactants, plasticizers, lubricants, glidants, chelating agents, coating agents and the like or mixtures thereof as extra-granular agents.
- the one or more pharmaceutically acceptable excipients is selected from diluents, binders, disintegrants, lubricants, glidants, surfactants, solubilizers, plasticizers, stabilizing agents, antioxidants, sweeteners, and any combination thereof.
- the percentage of compound or amorphous solid dispersion present is from 1% to 90% (w/w) (e.g., from 1% to 19%, from 10% to 19%, from 10% to 20%, from 10% to 30%, from 10% to 40%, from 10% to 50%, from 10% to 60%, from 10% to 70%, from 10% to 80%, from 10% to 90%, from 20% to 30%, from 20% to 40%, from 20% to 50%, from 20% to 60%, from 20% to 70%, from 20% to 80%, from 20% to 90%, from 21% to 30%, from 21% to 34%, from 21% to 40%, from 21% to 50%, from 21% to 60%, from 21% to 70%, from 21% to 80%, from 21% to 90%, from 30% to 40%, from 30% to 50%, from 30% to 60%, from 30% to 70%, from 30% to 80%, from 30% to 90%, from 36% to 40%, from 36% to 49%, from 36% to 60%, from 36% to 70%, from 36% to 80%, from 36% to 90%, from 40%
- the percentage of the compound or amorphous solid dispersion in the subject pharmaceutical composition is from 30% to 50% (w/w) (e.g., from 30% to 48%, from 30% to 45%, from 30% to 42%, from 30% to 40%, from 35% to 50%, from 35% to 48%, from 35% to 45%, from 35% to 44%, from 35% to 43%, from 35% to 42%, from 35% to 41%, from 35% to 40%, from 36% to 40%, and from 37% to 40%).
- the percentage of the compound or amorphous solid dispersion present is from 30% to 50% (w/w), such as 35 to 45% (w/w).
- the percentage of amorphous solid dispersion present is from 35 to 45%, such as 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, or 45% (w/w). In some embodiments of the pharmaceutical composition, the percentage of amorphous solid dispersion present is 40% (w/w). 3.4.1.
- compositions that include a subject compound of formula (I) or amorphous solid dispersion as described herein, and one or more pharmaceutically acceptable excipients or carriers including but not limited to, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers, surfactants, disintegrants, lubricants, binders, glidants, adjuvants, and combinations thereof suitable for oral administration.
- inert solid diluents and fillers including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers, surfactants, disintegrants, lubricants, binders, glidants, adjuvants, and combinations thereof suitable for oral administration.
- diluents including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers, surfactants, disintegrants, lub
- compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington: The Science and Practice of Pharmacy, 23rd Edition, ISBN-13: 978-0128200070); and Modern Pharmaceutics, Marcel Dekker, Inc., 4th Ed. (G. S. Banker & C. T. Rhodes, Eds.).
- the pharmaceutical compositions provided in accordance with the present disclosure can be configured for oral administration.
- the pharmaceutical compositions may be administered by oral administration. Administration may be via an oral suspension of powder or granules, an oral disintegrating tablet (ODT), or the like.
- ODT oral disintegrating tablet
- the subject pharmaceutical composition is in the form of a powder.
- the subject pharmaceutical composition is in the form of granules.
- the subject pharmaceutical composition is in the form of a powder or granules which has been reconstituted as an oral suspension.
- the subject pharmaceutical composition is reconstituted in a food or a beverage.
- the pharmaceutical composition is in the form of an oral disintegrating tablet (ODT).
- ODT oral disintegrating tablet
- the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a sachet, or other container.
- the excipient serves as a diluent, it can be in the form of a solid, semi-solid or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient.
- the pharmaceutical composition may be formulated for immediate release or sustained release.
- a “sustained release formulation” is a formulation which is designed to slowly release a therapeutic agent in the body over an extended period of time
- an “immediate release formulation” is a formulation which is designed to quickly release a therapeutic agent in the body over a shortened period of time.
- the immediate release formulation may be coated such that the therapeutic agent is only released once it reached the desired target in the body (e.g., the stomach).
- the pharmaceutical composition is formulated for immediate release.
- the pharmaceutical composition may further comprise pharmaceutical excipients such as fillers or diluents, binders, glidants, disintegrants, lubricants, solubilizers, and combinations thereof. Some examples of suitable excipients are described herein.
- the tablet When the pharmaceutical composition is formulated into a tablet, the tablet may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
- the pharmaceutical composition comprises a diluent or a filler, such as a carbohydrate or a protein filler.
- the diluent is selected from the group consisting of dicalcium phosphate, cellulose, microcrystalline cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, compressible sugars, dibasic calcium phosphate dehydrate, lactose, lactose monohydrate, sucrose, mannitol, sorbital, starch from corn, wheat, rice, potato or other plants, tribasic calcium phosphate, a gum (e.g., Arabic or tragacanth), proteins (e.g., gelatin or collagen) and combinations thereof.
- a gum e.g., Arabic or tragacanth
- proteins e.g., gelatin or collagen
- the diluent is selected from microcrystalline cellulose, dicalcium phosphate, cellulose, compressible sugars, dibasic calcium phosphate dehydrate, lactose, lactose monohydrate, lactose anhydrous, mannitol, tribasic calcium phosphate, a partially pregelatinized starch and combinations thereof.
- the pharmaceutical composition comprises one or more diluents in an amount from 10 to 70% w/w, or from 20 to 70% w/w, or from 25% to 70% w/w, or from 30 to 70% w/w, or from 35 to 70% w/w, or from 40 to 70% w/w, or from 45 to 65% w/w, or from 45 to 60% w/w, or from 50 to 60% w/w.
- one or more diluents is present in an amount of 50 to 60% w/w, such as 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59% or 60% w/w.
- one or more diluents is present in an amount of 50 to 51% w/w. In some embodiments, one or more diluents is present in an amount of 58 to 59% w/w.
- the diluent is microcrystalline cellulose present in an amount of from 50 to 60% w/w, such as 50 to 51% w/w, 51 to 52% w/w, 52 to 53% w/w, 53 to 54% w/w, 54 to 55% w/w, 55 to 56% w/w, 56 to 57% w/w, 57 to 58% w/w, 58 to 59% w/w, or 59 to 60% w/w.
- the diluent is mannitol present in an amount of 50 to 60% w/w, such as 50 to 51% w/w, 51 to 52% w/w, 52 to 53% w/w, 53 to 54% w/w, 54 to 55% w/w, 55 to 56% w/w, 56 to 57% w/w, 57 to 58% w/w, 58 to 59% w/w, or 59 to 60% w/w.
- 50 to 60% w/w such as 50 to 51% w/w, 51 to 52% w/w, 52 to 53% w/w, 53 to 54% w/w, 54 to 55% w/w, 55 to 56% w/w, 56 to 57% w/w, 57 to 58% w/w, 58 to 59% w/w, or 59 to 60% w/w.
- the diluent is a pregelatinized starch (e.g., starch 1,500) present in an amount of 50 to 60% w/w, such as 50 to 51% w/w, 51 to 52% w/w, 52 to 53% w/w, 53 to 54% w/w, 54 to 55% w/w, 55 to 56% w/w, 56 to 57% w/w, 57 to 58% w/w, 58 to 59% w/w, or 59 to 60% w/w.
- the diluent used has a combination of properties.
- the diluent can also acts as a binder and/or a disintegrant.
- the pharmaceutical composition comprises a disintegrant or solubilizing agent selected from cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof (e.g., sodium alginate), croscarmellose sodium, crospovidone, modified corn starch, pregelatinized starch, sodium starch glycolate, and combinations thereof.
- the pharmaceutical composition comprises one or more disintegrants in an amount from 1 to 10% w/w, or from 1 to 9% w/w, or from 1 to 8% w/w, or from 2 to 8% w/w, or from 4 to 6% w/w.
- one or more disintegrants is present in an amount of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% w/w.
- the disintegrant is croscarmellose sodium present in an amount of 4 to 6% w/w.
- the disintegrant is croscarmellose sodium present in an amount of 5% w/w.
- the pharmaceutical composition comprises a lubricant selected from the group consisting of calcium stearate, magnesium stearate, polyethylene glycol, sodium stearyl fumarate, stearic acid, and combinations thereof.
- the pharmaceutical composition comprises one or more lubricants in an amount from about 0.1 to about 2% w/w, or from about 0.5 to about 1.8% w/w, or from about 0.5 to about 1.5% w/w, or from about 0.5 to about 1.4% w/w, or from about 0.5 to about 1.3% w/w, or from about 0.5 to about 1.2% w/w, or from about 0.5 to about 1.1% w/w.
- the lubricant is sodium stearyl fumarate present in an amount of 0.5%, 0.6% w/w, 0.7% w/w, 0.8% w/w, 0.9% w/w, or 1.0% w/w. In some embodiments, the lubricant is sodium stearyl fumarate present in an amount of 1.0% w/w.
- the pharmaceutical composition comprises a glidant selected from the group consisting of colloidal silicon dioxide, talc, and combinations thereof.
- the pharmaceutical composition comprises one or more glidants in an amount from about 0.1 to about 2.5% w/w, or from about 0.5 to about 2.0% w/w, or from about 0.5 to about 1.5% w/w. In specific embodiments, one or more glidants is present in an amount of 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, or 1.5% w/w. In some embodiments, the glidant is colloidal silicon dioxide present in an amount of 1.5% w/w. [0159] In some embodiments, the pharmaceutical composition comprises a sweetener. In some embodiments, the sweetener is an artificial sweetener, such as sucralose.
- the pharmaceutical composition comprises one or more sweeteners in an amount from 1 to 10% w/w, or from 1 to 9% w/w, or from 1 to 8% w/w, or from 2 to 8% w/w, or from 4 to 6% w/w, or from 1 to 5% w/w, or from 1 to 2.5% w/w.
- one or more sweeteners is present in an amount of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% w/w.
- the sweetener is sucralose present in an amount of from 1.5 to 2.5% w/w. In some embodiments, the sweetener is sucralose present in an amount of from 2 to 3% w/w.
- the pharmaceutical composition comprises one or more surfactants. Suitable surfactants include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical dosage forms.
- polyethoxylated fatty acids and its derivatives for example, polyethylene glycol 400 distearate, polyethylene glycol-20 dioleate, polyethylene glycol 4-150 mono dilaurate, and polyethylene glycol—20 glyceryl stearate; alcohol—oil transesterification products, for example, polyethylene glycol—6 corn oil; polyglycerized fatty acids, for example, polyglyceryl—6 pentaoleate; propylene glycol fatty acid esters, for example, propylene glycol monocaprylate; mono and diglycerides, for example, glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, for example, polyethylene glycol—20 sorbitan monooleate and sorbitan monolaurate; polyethylene glycol alkyl ether or phenols, for example, polyethylene glycol—20 cetyl ether and polyethylene glycol—10-100 nonyl
- the pharmaceutical composition may include one or more plasticizers.
- Suitable plasticizers include polyethylene glycol, propylene glycol, polyethylene oxide, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol and monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, triethyl citrate, acetyl triethyl citrate, tributyl citrate and allyl glycolate.
- the pharmaceutical composition may include a coloring agent. Suitable coloring agents include dyes and pigments such as iron oxide red or yellow, titanium dioxide, talc. The concentration of coloring agent can range from about 0.1% to about 1% w/w of the total composition.
- the pharmaceutical composition may include a chelating agent. Suitable chelating agents include, one or more of, but not limited to ethylenediaminetetraacetic acid (EDTA), disodium EDTA and derivatives thereof, citric acid and derivatives thereof, niacinamide and derivatives thereof, and sodium desoxycholate and the like or mixtures thereof.
- EDTA ethylenediaminetetraacetic acid
- disodium EDTA and derivatives thereof citric acid and derivatives thereof, niacinamide and derivatives thereof, and sodium desoxycholate and the like or mixtures thereof.
- the pharmaceutical composition comprises the amorphous solid dispersion (e.g., as described herein), one or more diluents, one or more disintegrants, and one or more additional actives.
- the pharmaceutical composition comprises 30- 50% w/w of the amorphous solid dispersion, 40-70% w/w of one or more diluents, 1-10% w/w of one or more disintegrants, and up to 100% w/w of one or more additional additives.
- the pharmaceutical composition comprises 35-45% w/w of the amorphous solid dispersion, 50-60% w/w of one or more diluents, 4-6% w/w of one or more disintegrants, and up to 100% w/w of one or more additional additives.
- one or more additional additives includes a lubricant, a glidant and a sweetener.
- the pharmaceutical composition comprises:
- the pharmaceutical composition comprises: [0168] In some embodiments, the pharmaceutical composition includes 1 to 5% of a sweetener. In some embodiments, the sweetener is an artificial sweetener. In some embodiments, the sweetener is sucralose. [0169]
- the pharmaceutical compositions described herein can be formulated with a compound of formula (I), or an amorphous solid dispersion of TQS-168 (e.g., as described herein), as the sole pharmaceutically active ingredient in the composition or can be combined with other active ingredients (e.g., as described herein).
- the pharmaceutical composition is formulated into one or more suitable pharmaceutical preparations, such as oral suspensions, powders, granules, an oral disintegrating tablet (ODT), sustained release formulations or elixirs in sterile solutions or suspensions for parenteral administration, or as transdermal patch preparation and dry powder inhalers.
- suitable pharmaceutical preparations such as oral suspensions, powders, granules, an oral disintegrating tablet (ODT), sustained release formulations or elixirs in sterile solutions or suspensions for parenteral administration, or as transdermal patch preparation and dry powder inhalers.
- the amount of said salt to be administered and/or to be incorporated into a pharmaceutical composition needs to be adjusted to take account of the molecular weight difference between the free base and salt form.
- a pharmaceutical composition i.e., pharmaceutical dosage form
- compositions described herein are provided for administration to a subject, for example, humans or animals (e.g., mammals) in unit dosage forms, such as sterile parenteral (e.g., intravenous) suspensions containing suitable quantities of the compounds or pharmaceutically acceptable derivatives thereof.
- Pharmaceutical compositions are also provided for administration to humans and animals in unit dosage form, including powders, granules, oral or nasal solutions or suspensions and oil-water emulsions containing suitable quantities of the subject compounds or pharmaceutically acceptable derivatives thereof.
- the subject compounds and amorphous solid dispersions are, in certain embodiments, formulated and administered in unit-dosage forms or multiple-dosage forms.
- Unit-dose forms refers to physically discrete units suitable for human or animal (e.g., mammal) subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of the subject compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or filler. Examples of unit-dose forms include sachets, ampoules and syringes and individually packaged tablets. Unit-dose forms can be administered in fractions or multiples thereof.
- a multiple-dose form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dose form. Examples of multiple-dose forms include sachets, vials, or bottles.
- multiple dose form is a multiple of unit-doses which are not segregated in packaging.
- the subject pharmaceutical composition is formulated as powders, granules, tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, suitablefor ingestion by a subject.
- the pharmaceutical composition is formulated as a dragee, and dragee cores are provided with suitable coatings such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
- Dyestuffs or pigments may be added to the dragee coatings for product identification or to characterize the quantity of active compound (i.e., dosage).
- the subject pharmaceutical composition is formulated for oral use as push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin having a coating such as glycerol or sorbitol.
- Push-fit capsules can contain compounds and mixed excipients as described herein, e.g., diluents or binders such as microcrystalline cellulose, lubricants such as talc or magnesium stearate, and optionally stabilizers.
- the subject pharmaceutical composition is formulated for oral use as a powder or granules, the unit doses of which can be individually packaged in sachets.
- the powder or granules can contain an amorphous solid dispersion of TQS- 168 mixed excipients as described herein, e.g., diluents such as microcrystalline cellulose, disintegrants such as croscarmellose sodium, lubricants such as sodium stearyl fumarate, and, optionally one or more other excipients, such as glidants and sweeteners.
- the subject compounds and amorphous solid dispersions described herein are in a liquid pharmaceutical formulation.
- Liquid pharmaceutically administrable formulations can, for example, be prepared by dispersing, or otherwise mixing the active compounds and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, and the like, to thereby form a solution or suspension.
- a pharmaceutical composition provided herein to be administered can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, and pH buffering agents and the like.
- the pharmaceutical formulations are powders or granules, which can be reconstituted for administration as suspensions, emulsions and other mixtures. They can also be reconstituted and formulated as solids or gels.
- the pharmaceutical composition is formulated in as a solid dosage form, such as an oral disintegrating tablet, a tablet or a capsule.
- the disclosure relates to pharmaceutical compositions comprising subject compounds or amorphous solid dispersions for oral administration. 3.4.2.
- Pharmaceutical Dosage forms [0181] In some embodiments, there is provided a pharmaceutical dosage form comprising the pharmaceutical composition described herein.
- the disclosure provides for powders, granules, oral disintegrating tablets, tablets, pills, capsules, oral suspensions and the like, comprising the pharmaceutical compositions or dosage forms described herein. Accordingly, in some embodiments, the pharmaceutical dosage from is a solid dosage form. In certain cases, the solid dosage form is a powder.
- the capsule is in the form of granules.
- the solid dosage form is in the form of a power or granules packaged in individually labelled sachets containing a single dose.
- the dosage form is an oral disintegrating tablet (ODT).
- ODT oral disintegrating tablet
- the pharmaceutical dosage is formulated for immediate-release.
- the dosage form is formulated for modified-release portion.
- immediate-release refers to the rapid release of the majority of the therapeutic compound. Particularly useful conditions for immediate-release are release of at least or equal to about 80% of the therapeutic compound within thirty minutes after oral ingestion.
- the particular immediate-release conditions for a specific therapeutic compound will be recognized or known by one of ordinary skill in the art.
- modified-release refers to slower release of the majority of the therapeutic compound as compared to immediate release dosage forms.
- the particular modified- release conditions for a specific therapeutic compound will be recognized or known by one of ordinary skill in the art.
- the pharmaceutical compositions are manufactured by processes such as direct compression, wet granulation or dry granulation.
- the pharmaceutical compositions are in the form of oral dosage forms, such as solid oral dosage forms, including powders, granules, oral disintegrating tablets (ODT), oral suspensions, and multi-particulates.
- he pharmaceutical composition of the present disclosure is a granulate/particulate material.
- the granules/particles may be filled into a sachet or compressed into a tablet.
- the tablet may optionally be coated with an additional enteric polymer or an immediate-release coating.
- the extrudates/granules of the present disclosure may be formulated into any suitable dosage form, including but not limited to oral suspensions, gels, oral disintegrating tablets (ODTs), tablets, capsules, immediate release formulations, delayed release formulations, controlled release formulations, extended-release formulations, pulsatile release formulations, and mixed immediate and controlled release formulations.
- the tablets or pills of the present disclosure may be coated to provide a dosage form affording the advantage of prolonged action or to protect from the acid conditions of the stomach.
- the tablets may also be formulated for immediate release.
- the tablet comprises a film coating.
- a film coating may be useful for limiting photolytic degradation. Suitable film coatings are selected by routine screening of commercially available preparations.
- the film coating is a hypromellose-based coating.
- the coating comprises a film-forming agent, a plasticizer, a glidant and optionally one or more pigments.
- An exemplary film coating composition may comprise hydroxypropyl methylcellulose (HPMC), lactose monohydrate, titanium dioxide, and triglyceride 1,2,3-triacetoxypropane (triacetin).
- the film coating composition may comprise hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), talc, titanium dioxide and optionally iron oxide, including iron oxide red and/or yellow.
- the pharmaceutical dosage form comprises a compound or amorphous solid dispersion (e.g., as described herein) in a therapeutically effective amount.
- the pharmaceutical dosage form includes a subject amorphous solid dispersion (e.g., as described herein) comprising TQS-168 in an amount from 10-5000 mg.
- the pharmaceutical dosage form comprises 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg +/- 10% of TQS-168.
- the pharmaceutical dosage form comprises 1500 mg, 2000 mg, 2500 mg, 3000 mg, 3500 mg, 4000 mg, 4500 mg, or 5000 mg +/- 10% of TQS-168.
- the pharmaceutical dosage form includes a subject amorphous solid dispersion (e.g., as described herein) comprising TQS-168 in an amount of 25-2000 mg.
- the pharmaceutical dosage form comprises 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 900 mg, 925 mg, 950 mg, 975 mg, or 1000 mg of TQS-168.
- the pharmaceutical dosage form includes a subject amorphous solid dispersion (e.g., as described herein) comprising TQS-168 in an amount of 50 mg to 450 mg.
- the pharmaceutical dosage form comprises from 50 mg to 100 mg TQS-168, or from 100 mg to 150 mg TQS-168, or from 150 mg to 200 mg TQS-168, or from 250 mg to 300 mg TQS-168, or from 300 mg to 350 mg TQS-168, from 350 mg to 400 mg, or 400 mg to 450 mg of TQS-168.
- the pharmaceutical dosage form comprises 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or 200 mg +/- 10% of TQS-168.
- the pharmaceutical dosage form comprises 210 mg, 220 mg, 230, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, or 450 mg +/- 10% of TQS-168.
- the pharmaceutical dosage form comprises 50 mg +/- 10% of TQS-168. In an embodiment, the pharmaceutical dosage form comprises 100 mg +/- 10% of TQS-168. In an embodiment, the pharmaceutical dosage form comprises 150 mg +/- 10% of TQS-168. In some embodiments, the pharmaceutical dosage form comprises 200 mg +/- 10% of TQS-168. In some embodiments, the pharmaceutical dosage form comprises 300 mg +/- 10% of TQS-168. In some embodiments, the pharmaceutical dosage form comprises 400 mg +/- 10% of TQS-168. In some embodiments, the pharmaceutical dosage form comprises 450 mg +/- 10% of TQS-168.
- the pharmaceutical dosage form includes a subject compound of formula (I) (e.g., as described herein) in an amount from 10-5000 mg.
- the pharmaceutical dosage form comprises 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg +/- 10% of a compound of formula (I).
- the pharmaceutical dosage form comprises 1500 mg, 2000 mg, 2500 mg, 3000 mg, 3500 mg, 4000 mg, 4500 mg, or 5000 mg +/- 10% of a compound of formula (I).
- the pharmaceutical dosage form comprises one or more excipients (e.g., as described herein).
- the pharmaceutical dosage form comprises one or more diluents.
- the pharmaceutical dosage from comprises microcrystalline cellulose.
- the pharmaceutical dosage form comprises one or more diluents (e.g., microcrystalline cellulose) in an amount from 300 mg to 700 mg, such as 350 mg to 650 mg, 400 mg to 650 mg, 450 mg to 650 mg, or 500 to 600 mg.
- the diluent is present in an amount of 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, or 600 mg +/- 10%.
- the pharmaceutical dosage form comprises microcrystalline cellulose in an amount from 300 mg to 700 mg, such as 350 mg to 650 mg, 400 mg to 650 mg, 450 mg to 650 mg, or 500 to 600 mg.
- the microcrystalline cellulose is in an amount of 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, or 600 mg +/- 10%.
- the pharmaceutical dosage form comprises one or more disintegrants. In certain cases, the disintegrant is croscarmellose sodium.
- the pharmaceutical dosage form comprises a disintegrant in an amount from 15 mg to 65 mg, such as about 15 mg to 60 mg, 20 mg to 60 mg, 25 mg to 60 mg, 30 mg to 60 mg, 35 to 55 mg, or about 40 to 50 mg.
- the pharmaceutical dosage from comprises a disintegrant in an amount of from 45 mg to 55 mg, such as 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, or 55 mg +/- 10%.
- the disintegrant is in an amount of 50 mg.
- the pharmaceutical dosage form comprises croscarmellose sodium in an amount from 15 mg to 65 mg, such as about 15 mg to 60 mg, 20 mg to 60 mg, 25 mg to 60 mg, 30 mg to 60 mg, 35 to 55 mg, or about 40 to 50 mg.
- the pharmaceutical dosage from comprises croscarmellose sodium in an amount of from 45 mg to 55 mg, such as 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, or 55 mg +/- 10%.
- the croscarmellose sodium is in an amount of 50 mg.
- the pharmaceutical dosage form comprises one or more lubricants.
- the lubricant is sodium stearyl fumarate.
- the pharmaceutical dosage form comprises a lubricant in an amount from 1 mg to 15 mg, such as 2 to 12 mg, 2 to 10 mg, 3 to 10 mg, 4 to 10 mg, or 5 to 10 mg.
- the pharmaceutical dosage from comprises a lubricant in an amount from 5 mg to 10 mg, such as 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg +/110%. In a specific embodiment, the lubricant is present in an amount of 10 mg.
- the pharmaceutical dosage form comprises sodium stearyl fumarate in an amount from 1 mg to 15 mg, such as 2 to 12 mg, 2 to 10 mg, 3 to 10 mg, 4 to 10 mg, or 5 to 10 mg.
- the pharmaceutical dosage from comprises sodium stearyl fumarate in an amount from 5 mg to 10 mg, such as 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg +/110%.
- the sodium stearyl fumarate is in an amount of 10 mg.
- the pharmaceutical dosage form comprises one or more glidants. In some cases, the glidant is colloidal silicon dioxide.
- the pharmaceutical dosage form comprises a glidant in an amount from 5 mg to 25 mg, such as about 10 to 25 mg, 10 to 20 mg, or 15 to 20 mg.
- the pharmaceutical dosage from comprises a glidant in an amount from 15 to 20 mg, such as 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg +/- 10%.
- the glidant is present in an amount of 15 mg.
- the glidant is present in an amount of 20 mg.
- the pharmaceutical dosage form comprises colloidal silicon dioxide in an amount from 5 mg to 25 mg, such as about 10 to 25 mg, 10 to 20 mg, or 15 to 20 mg.
- the pharmaceutical dosage form comprises colloidal silicon dioxide in an amount from 15 to 20 mg, such as 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg +/- 10%. In an embodiment, the colloidal silicon dioxide is present in an amount of 15 mg. In an embodiment, the colloidal silicon dioxide is present in an amount of 20 mg. [0203] In some embodiments, the pharmaceutical dosage form comprises one or more sweeteners. In some cases, the sweetener is sucralose. In some embodiments, the pharmaceutical dosage form comprises a sweetener in an amount from 1 mg to 30 mg, such as about 1 to 25 mg, 1 to 23 mg, 5 to 25 mg, 10 to 25 mg, 15 to 25 mg, or 20 to 25 mg.
- the pharmaceutical dosage from comprises a sweetener in an amount from 20 to 25 mg, such as 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, or 25 mg +/- 10%. In an embodiment, the sweetener is present in an amount of 22-23 mg.
- the pharmaceutical dosage form comprises sucralose in an amount from 1 mg to 30 mg, such as about 1 to 25 mg, 1 to 23 mg, 5 to 25 mg, 10 to 25 mg, 15 to 25 mg, or 20 to 25 mg. In some embodiments, the pharmaceutical dosage form comprises sucralose in an amount from 20 to 25 mg, such as 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, or 25 mg +/- 10%.
- the colloidal silicon dioxide is present in an amount of 15 mg.
- the sucralose is present in an amount of 22-23 mg.
- the pharmaceutical dosage form comprises a) 50-400 mg of an amorphous solid dispersion of TQS-168 (e.g., as described herein); b) 300-700 mg of a diluent; c) 15-65 mg of a disintegrant; d) 1-15 mg of a lubricant; e) 5-25 mg of a glidant; and f) optionally 1-25 mg of a sweetener.
- the pharmaceutical dosage form comprises a) 50-400 mg of an amorphous solid dispersion of TQS-168 (e.g., as described herein); b) 300-700 mg of microcrystalline cellulose; c) 15-65 mg of croscarmellose sodium; d) 1-15 mg of sodium stearyl fumarate; e) 5-25 mg of colloidal silicon dioxide; and f) optionally 1-25 mg of sucralose.
- the pharmaceutical dosage form includes an amorphous solid dispersion of TQS-168 (e.g., as described herein) as the sole active ingredient.
- the pharmaceutical dosage form includes an amorphous solid dispersion of TQS- 168 (e.g., as described herein) in combination with other active agents (e.g., as described herein).
- the subject pharmaceutical dosage form e.g., as described herein
- the pharmaceutical dosage from comprises 2-(4-tert-butylphenyl)- 1H-benzo[d]imidazol-5-ol (Compound 26) having the formula:
- the pharmaceutical dosage form includes a compound of formula (I) as the sole active ingredient.
- the pharmaceutical dosage form includes a compound of formula (I) in combination with other active agents (e.g., as described herein).
- the pharmaceutical composition, or pharmaceutical dosage form as described herein is free of negative drug-drug interactions.
- the pharmaceutical composition, or pharmaceutical dosage form is free of negative drug-drug interactions with other active agents.
- the pharmaceutical composition, or pharmaceutical dosage form as described herein is administrable without regard to food and with or without regard to the patient being on another therapeutic agent. 3.5. Dosage Regimens 3.5.1.
- the compound of formula (I) or TQS-168 in the subject formulations is administered in a dose that is independent of subject weight or surface area (flat dose).
- the flat dose is 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, or 1 mg.
- the flat dose is 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg.
- the flat dose is 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg.
- the flat dose is 25 mg, 30 mg, 40 mg, or 50 mg. In some embodiments, the flat dose is 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg. In some embodiments, the flat dose is 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg. [0214] In some embodiments, the flat dose is 0.1 – 1 mg, 1 – 10 mg, 10 – 15 mg, 15 – 20 mg, 20 – 30 mg, 30 – 40 mg, or 40 – 50 mg.
- the flat dose is 1 – 50 mg, 50 – 100 mg, 100 mg – 200 mg, 200 mg – 300 mg, 300 mg – 400 mg, 400 mg – 500 mg, 500 mg – 600 mg, 600 mg – 700 mg, 700 mg – 800 mg, 800 mg – 900 mg, or 900 mg – 1000 mg. [0215] In some embodiments, the flat dose is 10 – 5000 mg.
- the dose is 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg.
- the dose is 1500 mg, 2000 mg, 2500 mg, 3000 mg, 3500 mg, 4000 mg, 4500 mg, or 5000 mg. [0216]
- the flat dose is 25 – 2000 mg.
- the dose is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 900 mg, 925 mg, 950 mg, 975 mg, or 1000 mg.
- the flat dose is 150 mg.
- the compound of formula (I) (e.g., as described herein); or the TQS-168 in the subject formulations (e.g., as described herein), is administered using a weight- based dose.
- the subject compound is administered in an amount of at least 0.5 mg/kg. In certain embodiments, the subject compound is administered in an amount of at least 1 mg/kg. In certain embodiments, the dose is at least 2 mg/kg, at least 3 mg/kg, at least 4 mg/kg, at least 5 mg/kg, at least 6 mg/kg, at least 7 mg/kg, at least 8 mg/kg, at least 9 mg/kg, or at least 10 mg/kg.
- the dose is at least 10 mg/kg. In certain embodiments, the dose is at least 15 mg/kg, at least 20 mg/kg, at least 25 mg/kg, 30 mg/kg, at least 35 mg/kg, at least 40 mg/kg, at least 45 mg/kg, at least 50 mg/kg, at least 55 mg/kg, at least 60 mg/kg, at least 65 mg/kg, at least 70 mg/kg, at least 75 mg/kg, at least 80 mg/kg, at least 85 mg/kg, at least 90 mg/kg, at least 95 mg/kg, at least 100 mg/kg, at least 150 mg/kg, at least 175 mg/kg, or at least 200 mg/kg.
- the dose is 0.5 mg/kg to 100 mg/kg per day. In some embodiments, the dose is 2 mg/kg to 100 mg/kg per day. In some embodiments, the dose is 25 mg/kg to 1000 mg/kg per day. In certain embodiments, the dose is 25 mg/kg. 3.5.2.
- Dose Regimen [0221] The compound of formula (I) (e.g., as described herein) or the subject formulation comprising TQS-168 (e.g., as described herein) can be administered in a single dose or in multiple doses.
- An exemplary dosage form may be a powder, granules (e.g., powder or granules reconstituted in a food or beverage for oral administration), an oral suspension, or an oral disintegrating tablet, taken from one to six times daily.
- the pharmaceutical dosage form is administered once daily.
- the pharmaceutical dosage form is administered twice daily.
- the pharmaceutical dosage form is administered three times daily.
- the pharmaceutical dosage form is administered four times daily.
- the pharmaceutical dosage form is administered five times daily.
- the pharmaceutical dosage form is administered six times daily. [0222]
- multiple doses of the pharmaceutical dosage form are administered.
- the frequency of administration of the dosage form can vary depending on any of a variety of factors, e.g., severity of the symptoms, etc.
- the subject dosage form is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid).
- the subject dosage form is administered twice a day (bid).
- the subject dosage form is administered three times a day (tid).
- the duration of administration of a pharmaceutical dosage from, e.g., the period of time over which the subject compound is administered, can vary, depending on any of a variety of factors, e.g., patient response, etc.
- an active agent can be administered over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, or from about two months to about four months, or more.
- dose levels can vary as a function of the specific compound, the severity of the symptoms and the susceptibility of the subject to side effects. Dosages for a given compound are readily determinable by those of skill in the art by a variety of means.
- the dosage form is administered intravenously.
- the subject compound or formulation is administered once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 14 days, once every 21 days, once every 28 days, or once a month.
- the subject compound o formulation is administered twice a day, twice every 2 days, twice every 3 days, twice every 4 days, twice every 5 days, twice every 6 days, twice every 7 days, twice every 14 days, twice every 21 days, twice every 28 days, or twice a month.
- the subject compound or formulation is administered once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 14 days, once every 21 days, once every 28 days, or once a month.
- the compound of Formula I is administered twice a day, twice every 2 days, twice every 3 days, twice every 4 days, twice every 5 days, twice every 6 days, twice every 7 days, twice every 14 days, twice every 21 days, twice every 28 days, or twice a month.
- the subject compound is administered at a daily oral dose of 100- 1000 mg. In some embodiments, the compound is administered at a daily oral dose of 200-800 mg.
- the compound is administered at a daily oral dose of 300-700 mg. In some embodiments, the compound is administered at a daily oral dose of 300-600 mg. In some embodiments, the compound is administered at a daily oral dose of 400-600 mg. In some embodiments, the compound is administered at a daily oral dose of 400-500 mg. [0228] In various embodiments, the subject compound is administered at a daily oral dose of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg. In certain embodiments, the compound is administered at a daily oral dose of 100 mg.
- the compound is administered at a daily oral dose of 200 mg. In certain embodiments, the compound is administered at a daily oral dose of 400 mg. In certain embodiments, the compound is administered at a daily oral dose of 450 mg. In certain embodiments, the compound is administered at a daily oral dose of 500 mg. In certain embodiments, the compound is administered at a daily oral dose of 750 mg. In certain embodiments, the compound is administered at a daily oral dose of 1000 mg. [0229] In some embodiments, the pharmaceutical dosage form comprises 100-200 mg the subject compound, and is administered orally 1-3 times daily. In certain embodiments, the dosage form is administered 3 times daily.
- the pharmaceutical dosage form comprises 200-300 mg the subject compound, and is administered orally 1-3 times daily. In certain embodiments, the dosage form is administered 2 times daily. [0231] In some embodiments, the pharmaceutical dosage form comprises 300-400 mg the subject compound, and is administered orally 1-3 times daily. In certain embodiments, the dosage form is administered 2 times daily. [0232] In some embodiments, the pharmaceutical dosage form comprises 400-500 mg the subject compound, and is administered orally 1-3 times daily. In certain embodiments, the dosage form is administered once daily. 3.6. Additional Agents [0233] In some embodiments, the methods of the present disclosure further comprise administering an effective amount of at least one additional active agent.
- the additional active agent is selected from an agent approved for the treatment of a hemoglobinopathy. In some cases, the agent is approved for the treatment of a sickle cell disease. In certain embodiments, the one or more additional agents is selected from hydroxyurea, L-glutamine, crizanlizumab and voxelotor, or pharmacutically acceptable salts there of. [0234] In some embodiments, the additional active agent is hydroxyurea. [0235] In some embodiments, the additional active agent is L-glutamine. [0236] In some embodiments, the additional active agent is crizanlizumab. [0237] In some embodiments, the additional active agent is voxelotor.
- the compound of formula (I) e.g., as described herein or the formulation of TQS-168 (e.g., as described herein) in combination with one or more additional active agents (e.g., as described herein) has an additive effect on HbF production.
- the compound of formula (I) e.g., as described herein
- the formulation of TQS-168 e.g., as described herein
- one or more additional active agents e.g., as described herein
- the compound of formula (I) is administered in combination with one or more additional agents selected from hydroxyurea, L- glutamine, crizanlizumab and voxelotor.
- the pharmaceutical composition comprising an amorphous solid dispersion of TQS-168 is administered in combination with one or more additional agents selected from hydroxyurea, L-glutamine, crizanlizumab and voxelotor.
- the compound of formula (I) is administered in combination with hydroxyurea.
- the pharmaceutical composition comprising an amorphous solid dispersion of TQS-168 is administered in combination with hydroxyurea.
- the compound of formula (I) is administered in combination with L-glutamine.
- the pharmaceutical composition comprising an amorphous solid dispersion of TQS-168 is administered in combination with L- glutamine.
- the compound of formula (I) is administered in combination with crizanlizumab.
- the pharmaceutical composition comprising an amorphous solid dispersion of TQS-168 is administered in combination with crizanlizumab.
- the compound of formula (I) is administered in combination with voxelotor.
- the pharmaceutical composition comprising an amorphous solid dispersion of TQS-168 is administered in combination with voxelotor. 3.7. Definitions [0250] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs.
- solid dispersion is meant a molecular dispersion of a compound, particularly a drug substance within a carrier.
- the term solid dispersion in general means a system in solid state comprising at least two components, wherein one component is dispersed substantially evenly throughout the other component(s).
- solid dispersions may be the dispersion of one or more active ingredients in an inert carrier or matrix at solid state, prepared by the melting, solvent, or melting-solvent methods.
- the drug in a solid dispersion, the drug may be present in a molecular state, colloidal state, metastable state, or an amorphous state. Formation of a molecular dispersion may provide a means of reducing the particle size to nearly molecular levels (i.e., there are no particles).
- a subject can be a mammal such as a non-primate (e.g., cows, pigs, horses, cats, dogs, goats, rabbits, rats, mice, etc.) or a primate (e.g., monkey and human), for example a human.
- the subject is a mammal, e.g., a human, diagnosed with a disease or disorder provided herein.
- the subject is a mammal, e.g., a human, at risk of developing a disease or disorder provided herein.
- the subject is human.
- the terms “therapies” and “therapy” are used in their broadest sense understood in the clinical arts.
- the term “pharmaceutically acceptable” indicates that the material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. For example, it is commonly required that such a material be essentially sterile, e.g., for injectables.
- carrier refers to a glidant, diluent, adjuvant, excipient, or vehicle etc. with which the compound is administered, without limitation. Examples of carriers are described herein and also in Remington: The Science and Practice of Pharmacy (Remington: The Science and Practice of Pharmacy, 23rd Edition, ISBN-13: 978-0128200070).
- diluent refers to chemical compounds that are used to dilute the compound of interest prior to delivery. Diluents can also serve to stabilize compounds. Non-limiting examples of diluents include starch, saccharides, disaccharides, sucrose, lactose, polysaccharides, cellulose, cellulose ethers, hydroxypropyl cellulose, sugar alcohols, xylitol, sorbitol, maltitol, microcrystalline cellulose, calcium or sodium carbonate, lactose, lactose monohydrate, dicalcium phosphate, cellulose, compressible sugars, dibasic calcium phosphate dehydrate, mannitol, and tribasic calcium phosphate.
- binder when used herein relates to any pharmaceutically acceptable film which can be used to bind together the active and inert components of the carrier together to maintain cohesive and discrete portions.
- binders include hydroxypropyl cellulose, hydroxypropylmethylcellulose, povidone, copovidone, and ethyl cellulose.
- disintegrant refers to a substance which, upon addition to a solid preparation, facilitates its break-up or disintegration after administration and permits the release of an active ingredient as efficiently as possible to allow for its rapid dissolution.
- Non-limiting examples of disintegrants include maize starch, sodium starch glycolate, croscarmellose sodium, modified corn starch, sodium carboxymethyl starch, crospovidone, pregelatinized starch, and alginic acid.
- lubricant refers to an excipient which is added to a powder blend to prevent the compacted powder mass from sticking to the equipment during the tableting or encapsulation process. It aids the ejection of the tablet form the dies, and can improve powder flow.
- Non- limiting examples of lubricants include magnesium stearate, stearic acid, silica, fats, calcium stearate, polyethylene glycol, sodium stearyl fumarate, or talc; and solubilizers such as fatty acids including lauric acid, oleic acid, and C8/C10 fatty acid.
- film coating refers to a thin, uniform, film on the surface of a substrate (e.g., tablet). Film coatings are particularly useful for protecting the active ingredient from photolytic degradation.
- Non-limiting examples of film coatings include polyvinylalcohol based, hydroxyethyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate film coatings.
- glidant as used herein is intended to mean agents used in tablet and capsule formulations to improve flow-properties during tablet compression and to produce an anti-caking effect.
- Non-limiting examples of glidants include colloidal silicon dioxide, talc, fumed silica, starch, starch derivatives, and bentonite.
- the term “effective amount” or “therapeutically effective amount” refers to an amount that is sufficient to effect treatment, as defined herein, when administered to a mammal in need of such treatment.
- the therapeutically effective amount will vary depending upon the patient being treated, the weight and age of the patient, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
- unit dosage forms or “pharmaceutical dosage forms” refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a sachet or a tablet).
- treatment or “treating,” to the extent it relates to a disease or condition includes preventing the disease or condition from occurring, inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition.
- Treatment can involve administering a compound described herein to a subject diagnosed with a disease, and may involve administering the compound to a subject who does not have active symptoms.
- treatment may involve administering the compositions to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
- administer refers to the act of introducing the dosage form into the system of subject in need of treatment.
- administration and its variants are each understood to include concurrent and/or sequential introduction of the dosage form and the other active agents.
- Administration of any of the described dosage forms includes parallel administration, co-administration or sequential administration.
- the therapies are administered at approximately the same time, e.g., within about a few seconds to a few hours of one another.
- C 1 to C 20 hydrocarbon includes alkyl, cycloalkyl, polycycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, adamantyl, camphoryl and naphthylethyl. Hydrocarbyl refers to any substituent comprised of hydrogen and carbon as the only elemental constituents.
- Aliphatic hydrocarbons are hydrocarbons that are not aromatic; they may be saturated or unsaturated, cyclic, linear or branched. Examples of aliphatic hydrocarbons include isopropyl, 2-butenyl, 2-butynyl, cyclopentyl, norbornyl, etc.
- Aromatic hydrocarbons include benzene (phenyl), naphthalene (naphthyl), anthracene, etc.
- alkyl or alkylene is intended to include linear or branched saturated hydrocarbon structures and combinations thereof.
- Alkyl refers to alkyl groups from 1 to 20 carbon atoms, such as 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like.
- Cycloalkyl is a subset of hydrocarbon and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include cy-propyl, cy-butyl, cy-pentyl, norbornyl and the like. [0269] Unless otherwise specified, the term “carbocycle” is intended to include ring systems in which the ring atoms are all carbon but of any oxidation state.
- carbocycle refers to both non-aromatic and aromatic systems, including such systems as cyclopropane, benzene and cyclohexene;
- carbopolycycle refers to such systems as norbornane, decalin, indane and naphthalene.
- Carbocycle if not otherwise limited, refers to monocycles, bicycles and polycycles.
- Heterocycle means an aliphatic or aromatic carbocycle residue in which from one to four carbons is replaced by a heteroatom selected from the group consisting of N, O, and S. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
- a heterocycle may be non-aromatic (heteroaliphatic) or aromatic (heteroaryl).
- heterocycles include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran and the like.
- heterocyclyl residues include piperazinyl, piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl, thienyl (also historically called thiophenyl), benzothienyl, thiamorpholinyl, oxadiazolyl, triazolyl and tetrahydroquinolinyl.
- Alkoxy or alkoxyl refers to groups of from 1 to 20 carbon atoms, such as 1 to 10 carbon atoms, or 1 to 6 carbon atoms of a straight or branched configuration attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy and the like. Lower-alkoxy refers to groups containing one to four carbons. For the purpose of this application, alkoxy and lower alkoxy include methylenedioxy and ethylenedioxy.
- Oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy, 3,6,9- trioxadecyl and the like.
- oxaalkyl is intended as it is understood in the art [see Naming and Indexing of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, 196, but without the restriction of 127(a)], i.e. it refers to compounds in which the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds); it does not refer to doubly bonded oxygen, as would be found in carbonyl groups.
- thiaalkyl and azaalkyl refer to alkyl residues in which one or more carbons has been replaced by sulfur or nitrogen, respectively. Examples include ethylaminoethyl and methylthiopropyl.
- halogen means fluorine, chlorine, bromine or iodine atoms. In one embodiment, halogen may be a fluorine or chlorine atom.
- acyl refers to formyl and to groups of 1, 2, 3, 4, 5, 6, 7 and 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality. Examples include acetyl, benzoyl, propionyl, isobutyryl and the like. Lower-acyl refers to groups containing one to four carbons. The double bonded oxygen, when referred to as a substituent itself is called “oxo”.
- substituted refers to the replacement of one or more hydrogen atoms in a specified group with a specified radical. For example, substituted alkyl, aryl, cycloalkyl, heterocyclyl etc.
- Oxo is also included among the substituents referred to in “optionally substituted”; it will be appreciated by persons of skill in the art that, because oxo is a divalent radical, there are circumstances in which it will not be appropriate as a substituent (e.g., on phenyl).
- 1, 2, or 3 hydrogen atoms are replaced with a specified radical.
- more than three hydrogen atoms can be replaced by fluorine; indeed, all available hydrogen atoms could be replaced by fluorine.
- Substituents R n are generally defined when introduced and retain that definition throughout the specification and in all independent claims.
- % w/w refers to the weight of a component based on the total weight of a composition comprising the component. For example, if component A is present in an amount of 50% w/w in a 100 mg composition, component A is present in an amount of 50 mg.
- % w/w refers to the weight of a component based on the total weight of a composition comprising the component. For example, if component A is present in an amount of 50% w/w in a 100 mg composition, component A is present in an amount of 50 mg.
- the compounds provided herein may be enantiomerically pure, or be stereoisomeric or diastereomeric mixtures.
- the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configurations, or may be a mixture thereof. The chiral centers of the compounds provided herein may undergo epimerization in vivo.
- the present disclosure also encompasses all suitable isotopic variants of the compounds according to the present disclosure, whether radioactive or not.
- An isotopic variant of a compound according to the present disclosure is understood to mean a compound in which at least one atom within the compound according to the present disclosure has been exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass which usually or predominantly occurs in nature.
- isotopes which can be incorporated into a compound according to the present disclosure are those of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I.
- Particular isotopic variants of a compound according to the present disclosure especially those in which one or more radioactive isotopes have been incorporated, may be beneficial, for example, for the examination of the mechanism of action or of the active compound distribution in the body.
- Isotopic variants of the compounds according to the present disclosure can be prepared by various, including, for example, the methods described below and in the working examples, by using corresponding isotopic modifications of the particular reagents and/or starting compounds therein.
- any of the embodiments described herein are meant to include a salt, a single stereoisomer, a mixture of stereoisomers and/or an isotopic form of the compounds.
- the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, or 3 standard deviations.
- the term “about” or “approximately” means within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.25%, 0.2%, 0.1% or 0.05% of a given value or range. Unless otherwise specified, the term “about” means within plus or minus 10% of a the explicitly recited value, rounded either up or down to the nearest integer. 4. EXAMPLES [0282] The Examples in this section are offered by way of illustration, and not by way of limitation. The examples can represent only some embodiments, and it should be understood that the following examples are illustrative and not limiting. All excipients, unless otherwise specified, are as previously defined.
- Example 1 Synthesis of Compounds of Formula (I).
- Compounds of formula (I) may be synthesized using any convenient method. Methods which can be adapted for use in preparing compounds of this disclosure includes the exemplary synthetic methods described in Methods A-H of Banister et al. in PCT application No. PCT/US2019/045229, filed Aug.6, 2019, the disclosure of which is herein incorporated by reference in its entirety.
- Example 2 Preparation of a Spray Dried Dispersion (SDD) Formulation of 2-(4-tert-butylphenyl)-1H-benzimidazole (TQS-168) [0284] A spray-dried dispersion (SDD) of 2-(4-tert-butylphenyl)-1H-benzimidazole (TQS-168) having the composition set out in Table 4 was prepared by spray drying a feedstock formulation set out in Table 5.
- SDD Spray Dried Dispersion
- TQS-168 A spray-dried dispersion (SDD) of 2-(4-tert-butylphenyl)-1H-benzimidazole (TQS-168) having the composition set out in Table 4 was prepared by spray drying a feedstock formulation set out in Table 5.
- TQS-168 (45.0 g) was slowly added to 2-propanol (1791.1 g) with stirring, placed under a homogenizer (Silverson SL2 homogenizer) and stirred for 5 minutes or more until TQS-168 was fully dissolved. The reaction mixture was then removed from the homogenizer and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (Soluplus) (60.0 g) was slowly added with stirring, placed back under the homogenizer and stirred for 10 minutes or more until the Soluplus was fully dissolved.
- Soluplus polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer
- the reaction mixture was then removed from the homogenizer and amorphous silicon dioxide (Syloid® 244 FP) was slowly added with stirring, placed back under the homogenizer and stirred for an additional 15 minutes or more until the amorphous silicon dioxide was fully dispersed.
- the resulting suspension is referred to herein as the “Feedstock Formulation.”
- Manufacturing Procedure for Spray Dried Dispersion (SDD) Formulation of TQS-168 [0286]
- the spray dryer unit (ProCepT 4M8 Spray Dryer) was set up with a compressed air supply. Once the outlet temperature stabilized, the feed pump was initiated, and 2-propanol (blank solution) was sprayed through the nozzle as a fine spray into the collection chamber.
- the spray dryer parameters were adjusted to achieve a feed rate within the range set out in Table 6 below.
- the feedstock formulation was stirred under a homogenizer at a speed appropriate to maintain a homogenous dispersion without generating bubbles.
- the feedstock formulation was then sprayed through the nozzle as a fine spray into the collection chamber of the spray dryer unit (ProCepT 4M8 Spray Dryer, using parameters as set up with the blank solution and outlined in Table 4) where the solvent was evaporated quickly to generate particles containing TQS-168 polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (Soluplus) and silicon dioxide (Syloid® 244 FP) (SDD formulation of TQS-168).
- the feedstock formulation was replaced with 2- propanol (blank solution) and sprayed through the nozzle of the spray dryer for 5 minutes or more to allow collection of any remaining “feedstock formulation” within the air stream.
- Example 3 Oral Suspension of a Spray Dried Dispersion (SDD) Formulation of 2-(4-tert-butylphenyl)-1H-benzimidazole (TQS-168) [0288]
- Table 4 e.g., from 60-1000 mg
- Example 4 Preparation of a Hot-Melt Extrusion (HME) Formulation of 2-(4-tert-butylphenyl)-1H-benzimidazole (TQS-168) [0289]
- HME Hot-melt extrusion
- TQS-168 A hot-melt extrusion (HME) formulation of 2-(4-tert-butylphenyl)-1H-benzimidazole (TQS-168) having the composition set out in Table 7 was prepared as set out below.
- TQS-168 HME extrudate The TQS-168 blend was added to the feeder to fill approximately 3 ⁇ 4 of the feeder, and the extrudate was collected and discarded for approximately the first 5 minutes of the extrusion process.
- the feeder was refilled to maintain approximately 50% volume in the feeder throughout the process, and extrusion was continued until all the TQS-168 blend was extruded and collected (“TQS-168 HME extrudate”).
- TQS-168 HME extrudate was added to a U5 Quadro mill (set up with a screen size of 457 (mm) and an impeller speed of 5000 RPM), until all extrudate had passed the 457 mm screen to obtain milled granules of TQS-168.
- the milled granules of TQS-168 were then sieved using a 300 micron sieve and transferred into a blender shell (Pharmatech 2L blender shell). The resultant blender shell was secured in a blender (Pharmatech blender), blended for 5 minutes, and collected. 4.5.
- Example 5 Oral Suspension of a Hot-Melt Extrusion (HME) Formulation of 2-(4-tert-butylphenyl)-1H-benzimidazole (TQS-168)
- HME Hot-Melt Extrusion
- TQS-168 2-(4-tert-butylphenyl)-1H-benzimidazole
- Table 7 e.g., from 60-1000 mg
- vehicle Ora-Blend SF® purified water, sucrose, glycerin, sorbitol, flavoring, microcrystalline cellulose, sodium carboxymethylcellulose, xanthan gum, carrageenan, citric acid, sodium phosphate, simethicone, potassium sorbate and methylparaben
- Example 6 Preparation of a Spray Dried Dispersion (SDD) Blend Formulation of 2-(4-tert-butylphenyl)-1H-benzimidazole (TQS-168) General Manufacturing procedure for SDD blend formulations
- SDD Spray Dried Dispersion
- TQS-168 2-(4-tert-butylphenyl)-1H-benzimidazole
- the disintegrant, sweetener and lubricant were then weighed, sieved through a 250 ⁇ m sieve and transferred to the blending shell. The resultant mixture was blended at 25 rpm (Pharmatech blender) for approximately 60 minutes.
- the SDD blends of TQS-168 were then evaluated for bulk density, tapped density, Carr’s Index and Hausner ratio (see Tables 11-13 below) before filling into sachets. Sachets of each blend (10 sachets of each) were then submitted for content uniformity testing (see Table 14 below).
- Tables 9-10 The TQS-168 SDD blend formulation compositions are summarized in Tables 9-10.
- Table 13 shows the relationship between Carr Index (compressibility index) and powder flow properties.
- Table 14 shows the results of content uniformity testing for TQS-168 SDD blend formulations. 4.7.
- Example 7 Effects of subject compounds and formulations on human primary erythroid progenitor CD34 + cells [0298] The effects of the compounds and formulations described in Sections 3.2 and 3.3 hereinabove on human primary erythroid progenitor CD34 + cells are studies using methods adapted from Sun et al. Sun et al., Br J Haematol.197:97-109 (2022), the disclosure of which is herein incorporated by reference in its entirety. HbF-positive cells (F cells) are quantified by flow cytometry after compound exposure.
- Globin gene mRNA abundance is determined by quantitative real-time polymerase chain reaction (qRT-PCR).
- the tested compounds and formulations including 2-(4-tert-butylphenyl)-1H- benzo[d]imidazol-5-ol (Compound 26) and TQS-168, induce both fetal ⁇ -globin mRNA protein expression and percentage of HbF-positive cells (F cells) in human primary erythroid progenitor CD34 + cells. 4.8.
- Example 8 Effects of subject compounds and formulations on SCD mice [0300] The effects of the compounds and formulations described in Sections 3.2 and 3.3 on SCD mice are studied using methods adapted from Sun et al., Br J Haematol.197:97-109 (2022), the disclosure of which is herein incorporated by reference in its entirety. Relative mRNA abundance of PGC-1 ⁇ and globin gene expression are determined by quantitative real-time polymerase chain reaction (qRT-PC R).
- HbF-positive cells (F cells) in peripheral blood of treated SCD mice are quantified by flow cytometry [0301]
- the tested compounds and formulations including 2-(4-tert-butylphenyl)-1H- benzo[d]imidazol-5-ol (Compound 26) and TQS-168, induce expression of both the murine embryonic ⁇ h1-globin gene and the human ⁇ -globin gene expression in SCD mice.
- the subject compounds/formulations also induce F-cell population in the peripheral blood of SCD mice. 5.
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Abstract
La présente divulgation concerne des composés de 2-arylbenzimidazole et des compositions pharmaceutiques ou des formulations de ceux-ci pour le traitement d'hémoglobinopathies chez un sujet. Dans certains modes de réalisation, l'hémoglobinopathie est une drépanocytose (SCD). La présente divulgation concerne également des composés de 2-arylbenzimidazole et des compositions pharmaceutiques ou des formulations de ceux-ci pour augmenter la production d'hémoglobine fœtale (HbF) chez un sujet.
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